m
U.S. DEPARTMENT OF
HEALTH, EDUCATION, AND WELFARE
Public Health Service
National Institutes of Health
A
1/
ti, 1 S. NATIONAL INSTITUTES OF HEALTH
ANNUAL REPORT OF INTERNATIONAL ACTIVITIES
FISCAL YEAR 1975
Prepared by
John E. Fogarty International Center
for
Advanced Study in the Health Sciences
U.S. DEPARTMENT OF HEALTH, EDUCATION, AND WELFARE
Public Health Service
National Institutes of Health
DHEW Publication No. (NIH) 76-62
For sale by the Superintendent of Documents, U.S. Government
Printing Office, Washington, D.C. 20402
ft is
PREFACE
This document is the seventh annual report of inter-
national activities published by the John E. Fogarty Inter-
national Center for Advanced Study in the Health Sciences.
It contains a comprehensive narrative review and analysis
of the international activities undertaken by the National
Institutes of Health in FY 1975. Two companion booklets,
NIH International Awards for Biomedical Research and
Research Training/ FY 1975 and NIH Statistical Reference
Book of International Activities, FY 197 5 , supplement this
annual report.
Within this review, the many international activities
of the National Institutes of Health and their contribution
toward broadening the knowledge base of the biomedical
sciences dedicated to the improved health of American
citizens as well as those of other nations are discussed.
A significant part of NIH international activities, in-
cluding the participation of distinguished foreign scien-
tists in the Scholars-in-Residence program and Fogarty
International Center conferences and symposia, as well
as bilateral cooperation, was undertaken under the au-
spices of the Fogarty International Center. Other acti-
vities providing international biomedical cooperation
have been conducted under the administrative purview of
several institutes and divisions of NIH. These organiz-
ations have contributed to the substantive content of this
report with descriptive analyses of their activities,
thereby providing a guide to the various types of NIH
international programs.
One important aspect of international cooperation
that is very difficult to quantify, and one that has not
been included in this document, is the informal exchange
and sharing of information between professional colleagues
in the United States and overseas. This cooperation, of
course, is as valuable to the fulfillment of NIH mission
as those other, more formal international cooperative
activities described herein.
This document was prepared by the International Coop-
eration and Geographic Studies Branch, Fogarty International
Center, Dr. Joseph R. Quinn , Chief. This branch is re-
sponsible for the overall coordination within the Fogarty
International Center of activities involving other govern-
ments .
Milo D. Leavitt, Jr., M.D.
Director
Fogarty International Center
INTRODUCTION
It has been the policy of the National Institutes of
Health for many years to stimulate and support interna-
tional biomedical research. Since the end of World War
II, in particular, NIH also has sought to extend inter-
national biomedical cooperation, recognizing, of course,
that the exchange of data among scientists of many nations
is fundamental to scientific progress. Thus, substantial
research grant awards have contributed to the developing
of productive working relationships between NIH and foreign
laboratories. Other support of various kinds has also
been instrumental in bringing foreign scientific competence
to American science. Ultimately, these efforts seek to
broaden the knowledge base of the biomedical sciences
devoted to improved health for citizens of the United
States and those of other nations.
In pursuit of these research objectives NIH undertook
numerous international activities during fiscal year 1975.
In addition to the continuation of ongoing grant and train-
ing awards, NIH scientists attended many international
biomedical conferences, sponsored international symposia
and seminars of various scientific and associated bio-
medical problems, received distinguished foreign biomed-
ical scientists, and published several books and papers
advancing NIH research programs. The Fogarty International
Center, as the point of coordination for the international
activities of NIH, initiated or was involved in a sub-
stantial part of the international cooperation in the
biomedical sciences delineated in this report.
CONTENTS
Page
Preface ...«.., iii
Introduction i v
I. Fogarty International Center:
Concept and Programs i
Conference and Seminar Program 5
Scholars-in-Residence Program 10
International Visitors Center 12
International Research Exchange Program . . 13
Visiting Program 15
Special Foreign Currency Program 16
International Education Program 21
Gorgas Memorial Institute 28
Bilateral Agreements for Cooperation in
Biomedical Research 29
Geographic Health Studies 35
FIC as Coordinator for NIH International
Activities 40
II. International Cooperation in the Health
Sciences by Components of NIH
National Cancer Institute 45
National Heart and Lung Institute 61
National Institute of Allergy and Infectious
Diseases 79
National Institute of Arthritis, Metabolism,
and Digestive Diseases 99
National Institute of Child Health and
Human Development 105
National Institute of Environmental Health
Sciences Ill
Page
National Library of Medicine 121
NIH Assistance to WHO and PAHO 129
United States Fellows and Trainees
Abroad 131
Guest Workers 131
I
FOGARTY INTERNATIONAL CENTER
CONCEPT AND PROGRAMS
FOGARTY INTERNATIONAL CENTER:
CONCEPT AND PROGRAMS
In a speech before the Third National Conference on
World Health in September 1963, Representative John E.
Fogarty introduced the concept of a center to represent
"...the visible and tangible embodiment of the nation's
devotion to the use of science for peaceful purposes and
the good of mankind." He envisaged a study center that
would "... encompass conference facilities, laboratory and
study space, and the living quarters to permit the assembly
for discussion, study, and research of the outstanding
health scientists of the world." Representative Fogarty
died on January 10, 1967, before the realization of this
concept. After his death, however, then Congressman
Melvin Laird proposed the establishment of such a center
as a living memorial to Mr. Fogarty. The Congress and
the President approved this proposal, and on July 1, 1968,
the John E. Fogarty Center for Advanced Study in the
Health Sciences was realized.
The close of FY 1975 records the completion of the
seventh year of operations for the Fogarty International
Center. During the course of these years several programs
have emerged as the principal activities of the Center and
from which the Center has derived much of its character
in attempting to fulfill the concept of Representative
Fogarty and the Honorable Melvin Laird.
Generally, the Center's programs were designed to pro-
mote advanced study in the biomedical and related sciences
and to develop practical methods to utilize the knowledge
thus, gained to improve the health and well-being of our
contemporary society. The Center's programs encourage
interaction, study, cooperation, and collaboration within
the international biomedical community and provide oppor-
tunities for study and discussion of significant research,
public health, medical, and biomedically related social
and economic issues.
Specifically, the projects that constitute the general
programs delineated above and that have developed within
the Center over the past 7 years constitute a substantial
spectrum of research and administrative support activities.
One such program involves studies on preventive medicine
that ultimately seek to investigate 15 areas of preventive
medicine, including diseases of fetal development, trauma,
emergencies and emergency care, communicable diseases,
gastropathy, and endocrine and metabolic diseases. Another
highly relevant and successful project involves the compi-
lation and analyses of biomedicine and health care in a
number of selected countries, with special emphasis upon
the Soviet Union and the People's Republic of China.
Several studies covering various aspects of biomedicine
and health care in the Soviet Union and China have been
published over the past 7 years and several others are
planned or in progress.
Still another imaginative project undertaken by the
Center is the Scholars-in-Residence program whereby dis-
tinguished scholars undertake a period of residence at
the Center to engage in research, individual study, and
group interaction designed to produce original contribu-
tions toward advancing biomedical knowledge and to facili-
tate the exchange of ideas among biomedical scholars.
Also of considerable current and potential significance
is the bilateral cooperation in biomedical research with
19 foreign countries in which the Center serves to coor-
dinate efforts for the United States Government. Although
this cooperation is governed in most instances by agree-
ments between the United States and other governments,
there have been times when this cooperation has been
attained through more informal bilateral arrangements.
Thus far, this cooperation has yielded knowledge of foreign
biomedical research and health care, as well as direct
contributions to the advancement of American biomedical
knowledge by foreign scientists.
In addition to these programs and projects briefly
described above, the Center has engaged in several admin-
istrative programs designed to advance biomedical and
related scientific knowledge in the United States:
1. Special Foreign Currency program (Public Law 480),
which enables NIH to support biomedical research in
"excess currency" countries abroad;
2. International Visitors Center, which serves as a
focal point for the reception of foreign scientists;
3. International Research Exchange program, which
has provided numerous opportunities for highly qualified
foreign biomedical scientists to engage in advanced
research in leading research institutions in the United
States; and
4. International Education program, under which
arrangements are made in the United States for biomedical
training for foreign nationals receiving WHO and UN fellow-
ships in the health sciences.
Finally, during our short past, the Center has provided
a general coordinating function for all NIH international
activities. In this role, the Center has reviewed foreign
grants and contracts, published biomedical data from
scientific observers abroad, and disseminated information
to NIH obtained from participants in international scientific
conferences and symposia.
In summary, then, the Fogarty International Center
for Advanced Study in the Health Sciences is attempting:
1. To promote advanced study in the health sciences
through various mechanisms, such as conferences and
seminars, support of scholars in residence on NIH campus,
publications, and bilateral and multilateral cooperation;
2. To identify the legal, ethical, social , and eco-
nomic problems that may arise from continuing biomedical
research and to advance our understanding and insight into
these problems; and
3. To stimulate research concepts in specific fields
through interaction among the international and domestic
biomedical research community.
There follows a description, in some detail, of the
previously referenced FIC program and project operations
during FY 1975 through which the Fogarty International
Center staff sought to fulfill the several objectives set
forth above.
Conference and Seminar Program
As part of the advanced study concept, the Conference
and Seminar program sponsors interaction and collaboration
among members of the international biomedical community
and provides opportunities for study and discussion of
significant biomedical, public health, and related social
and economic issues.
In practice, the Conference program is developed
around current directions in medical, biological, and be-
havioral sciences. Many of the meetings are in direct
support of the research activities of the NIH, and criteria
for sponsoring of conferences include a broad interest
within the scientific objectives in addition to information
exchange, and international priority.
Conferences convened to date can be classified into
several conceptual areas: preventive medicine and health
care delivery, environmental health, medical education,
international health research and education, ethical and
social problems in biomedicine, and advanced topics in
biomedical research.
Preventive Medicine
and
Health Care Delivery
Improvement in the health status of the American
people depends in great measure on the design and applica-
tion of programs that emphasize the preventive aspects of
human disease problems. Although health authorities
generally agree with this thesis, a more precise defini-
tion is needed of effective methods or programs of preven-
tion, financial resources required to implement these
programs, and priorities to be assigned to research in
preventive methodology. The need to assemble expertise
in this field to elucidate mechanisms whereby the full
impact of preventive medicine can be brought to bear on
the solving of America's major health problems has been
emphasized by the Office of the Assistant Secretary, DHEW,
in the Forward Plan for Health.
Three years ago the Fogarty International Center ini-
tiated a series of comprehensive studies in preventive
medicine. These studies, oriented by disease category,
are charged to review and evaluate the state of knowledge
and research in the prevention and control of human disease;
identify knowledge gaps and areas requiring further research,
including analysis of financial resources, techniques,
and manpower; and identify problems encountered in apply-
ing preventive medicine and suggest corrective actions.
The first planning session of the organizational com-
mittee identified 15 major disease categories for detailed
review by individual subcommittees. Of the six subjects
selected for initial consideration, studies of diseases of
fetal development and the neonatal period, derangements
of dental health, communicable diseases, diabetes, and
obesity have been completed and published. Additional
subcommittees have been activated to consider renal disease,
nutritional derangements, arthritis, maternal and child
health, trauma, screening and health maintenance, and
economic impact of ill health.
In an effort to coordinate divergent activities in
preventive medicine, the Fogarty International Center has
also undertaken a cooperative program with the Association
of Teachers of Preventive Medicine. Designed to develop
resource material for departments of preventive medicine,
this program has the following objectives: to create
resource material for individual departments in adminis-
tration, teaching, research, and service; define depart-
ment goals and enhance collaborative activity among depart-
ments of preventive medicine and other departments of
health science schools; promote cooperative activities
among departments of preventive medicine via national
joint teaching, research, and service programs; and pro-
vide consultative services to other agencies. The Fogarty
Center has also cooperated with the Milbank Memorial Fund
in its study of higher education for public health.
Among the 10 subjects considered, all have been
completed and published:
-- New Health Practitioners
— Teaching of Chronic Illness and Aging
— Chronic Childhood Illness - Assessment of Outcome
— Behavioral Sciences
— Preventive and Community Medicine in Primary Care
-- Consumer Participation in Health Care
— Toward an Educated Health Consumer
— International and Extramural Teaching and Research
Resources in Preventive Medicine
— Academic Relationships Between Preventive Medicine
and Public Health
— National Teaching Resources in Preventive Medicine
To further assist coordination of preventive medicine
in the United States, the Fogarty Center sponsored a
National Conference on Preventive Medicine in June 1975,
in which over 200 specialists in preventive medicine and
allied fields participated. During the preceding year,
eight Task Forces developed position papers in the areas
of: historical perspective of preventive medicine in the
U.S.; theory and practice of prevention in environmental
health, delivery of preventive care in personal health
services, social determinants of human health, consumer
health education, training of health professionals for
prevention, economic impact of preventive medicine, and
quality control and evaluation. These task force reports
were reviewed by the conference participants and recom-
mendations were made for their implementation and for
subsequent planning. The conclusions of the Task Forces
were incorporated into DHEW Forward Plan for Health
1976-80.
Environmental Health
Conferences on environmental health topics have been
sponsored in collaboration with the National Institute of
Environmental Health Sciences. These meetings were in
response to increased awareness of the contribution of
the environment to disease processes and in support of
the U.S. delegation to the UN conference, "Man and the
Environment." The topics-controversy regarding the precise
effect of environmental pollutants, uncertainty about the
mechanisms by which they produce their effects, or simply
lack of information as to the extent of the problem-
explored the roles of metallic contaminants, mutagenic
agents, and multiple environmental factors in producing
disease and the contribution of environmental factors to
respiratory disease. These workshops have been made
available to the public by publication.
Medical Education
This conference series developed largely in response
to student unrest in the 1960's. This unrest reflected
the need to revise medical curricula, making education
more responsive to community needs. As a result, depart-
ments of community or social medicine were established and
family practice came to be recognized as a speciality.
The conferences sponsored by the Fogarty Center considered
the student pressure for curriculum reform internationally,
the role of biomedical research in the education of
physicians, and the relationships between health care and
medical education in the medical school. These conferences
have all been published.
International Health
Research and Education
Biomedical research and medical education are inex-
tricably linked and mutually dependent on one another for
their continued advancement and vitality. Institutions
of medical education serve several purposes, tradition-
ally represented by the triad of education, research,
and service. In addition to training those who will pro-
vide health care, medical schools strive to cultivate an
atmosphere conducive to research and to train those who
will pursue careers in research and teaching.
Central to the purposes is the belief that virtually
all countries share common problems and goals in educating
and training health care providers. Direction and leader-
ship are necessary in order to achieve the highest possible
standards of medical care. Differences in approach to that
goal are more a reflection of differences of cultural,
social, and economic characteristics than of purpose. It
is reasonable to believe that sharing ideas and experiences
can be mutually beneficial.
The general objectives of the program follow:
— To serve as a focal point within the Fogarty
International Center and the National Institutes of Health
for matters relating to international medical education
at both undergraduate and postgraduate levels;
— To accumulate, classify, and maintain information
about current and changing patterns of medical education
in advanced and developing, countries;
— To evaluate such information with respect to health
care problems and needs of individual countries and with^
in the framework of their socioeconomic, cultural, and
political characteristics;
— To compare systems of medical education with one
another and with established or changed patterns of
medical education in the United States;
— To initiate, support or assist the development
of individual or collaborative studies or programs
pertinent to its mission.
Ethical and Social Problems
in
Biomedicine
The Center has sponsored conferences on various social
and ethical problems arising from advances in biomedical
research and the application of these advances to medical
care. The Center is ideally suited to this role, since it
represents a nonpartisan meeting ground for discussion of
these controversial areas. Topics considered have included
changing family structure and control of human repro-
duction; new technological abilities for early diagnosis
of human genetic disease and detection of persons who
may transmit genetic disease to their offspring; the
prospects for treatment of patients with genetic disease,
and the ethical issues involved in genetic counseling;
and the health hazards involved in experimentation with
oncogenic and infectious viruses.
Advanced Topics in Biomedical Research
Support of meetings in this category is in
recognition of the important role of research in the
understanding of disease processes and in the development
of early detection and better treatment of illness. Many
of these conferences have provided support for the research
activities of the various NIH institutes.
In addition, Fogarty Scholars and U.S. and foreign
academicians have participated in identifying key problems
in basic and clinical research that should be explored
by bringing together scientists in various fields.
Conferences sponsored recently include;
-<- Cell Surfaces and Malignancy
— Chemistry and Biology of the Kallikrein-Kinen
System
10
— Modification of Host Immune Resistance in the
Prevention and Treatment of Neoplasia
— Structure and Function of Fluorescing Cells
— Chemistry, Biology, and Political Aspects of Uses
of the Atmosphere
Scholars-in-Residence Program
Crucial to the study center concept, this program
facilitates the work of individual scholars and the ex-
change of ideas among scholars, distinguished science
leaders, science administrators, and promising young
scientists. Individuals accepting an invitation to par-
ticipate in the program are known as "Fogarty Scholars"
during their period in residence. Invitations are limited
to persons of distinction who - in the judgment of the
director of the Center, his staff, and advisors - have the
educational and cultural background plus research exper-
ience to make significant contributions to advanced study
in national boundaries.
Scholars and invited participants are not limited
solely to experience in the biomedical disciplines; they
may also consider studying philosophic, social, economic,
or legal issues related to health science. While in resi-
dence each scholar participates in one or more of the
following types of activity:
1. Individual study : The scholar may make an assess-
ment of the state of the art or a prospective study in a
specific field. This approach can be directed toward
preparation of a book, monograph, or scientific report.
Working primarily on an individual basis, the scholar is
encouraged to participate in other NIH workshops, confer-
ences, and seminars.
2. Group Interaction : The scholar might prefer to
collaborate with other scholars and invited consultants in
considering a common topic for the purpose of developing
recommendations or suggestions for the advancement of
biomedical knowledge.
3. Research : At the invitation of an institute, the
scholar might choose to spend a portion of his time in the
laboratory. As a Fogarty Scholar, however, he is encouraged
to participate in FIC-sponsored workshops, conferences, and
seminars when appropriate .
The sum of $210,867 was expended from Fogarty Inter-
national Center FY 1975 funds for the Scholars-in-Residence
program. The following 14 distinguished scientists were
11
Scholars-in-Residence during FY 1975:
Dr. Karl Beyer, Visiting Professor, Department of
Pharmacology, Milton S. Hershey Medical Center, Penn-
sylvania State University, Hershey, Pennsylvania.
Dr. Daniel Bovet, Professor of Psychobiology , Uni-
versity of Rome, Rome, Italy.
Dr. Ronald V. Christie, Professor Emeritus, Office
of the Dean, McGill University, Montreal, Quebec, Canada.
Dr. Hugh Davson, Honorary Research Fellow, Depart-
ment of Physiology, University College London, London,
England.
Dr. Olavi Eranko, Professor and Chairman, Department
of Anatomy, University of Helsinki, Helsinki, Finland.
Dr. George E. Godber, (Former) Chief Medical Officer,
Department of Health and Social Security, United Kingdom,
London, England.
Dr. Ragnar Granit, Professor Emeritus, Nobel Insti-
tute for Physiology, Karolinska Institutet, Stockholm,
Sweden .
Dr. Gordon G. Hammes, Professor and Chairman, Depart-
ment of Chemistry, Cornell University, Ithaca, New York.
Dr. Abraham Horwitz, Director Emeritus, Pan American
Sanitary Bureau, Washington, D.C.
Dr. Elvin A. Kabat, Professor, Department of Micro-
biology, College of Physicians and Surgeons, Columbia
University, New York, New York.
Dr. Herman M. Kalckar, Visiting Professor, Biological
Chemistry, Harvard University Medical School, Boston,
Massachusetts .
Dr. Charles P. Leblond, Professor and Chairman,
Department of Anatomy, McGill University, Montreal, Quebec,
Canada.
Dr. Dirk W. Van Bekkum, Director, Radiobiological
Institute, Institute for the Organization for Health
Research, Rijwijk, The Netherlands.
Dr. Paul C. Zamecnik, Director, Colis P. Huntington
Labs, Massachusetts General Hospital, Boston, Massachusetts
12
International Visitors Center
This major program service of the Fogarty Interna-
tional Center receives scientists from all parts of the
world. The Visitors Center is responsible for developing
appointments for foreign scientists and dignitaries at
NIH and coordinating them with their visits to other
research centers.
During FY 1975, 195 of the 247 visitors were from 43
foreign countries and represented every part of the
academic world. The U.S.S.R. sent 24, the largest number
of visitors; followed by the People's Republic of China
with 19, France with 17, the Federal Republic of Germany
with 14, and Italy with 13. Among the distinguished
visitors to NIH were Mr. Osman Dana, Minister of Health
of Lebanon; Prof. Hubert Curien, Director, General Dele-
gation for Scientific and Technical Research (DGRST) ,
France; Dr. Philippe Laudat, Scientific Director of INSERM,
France; Dr. A. P. Burger, Vice President of CSIR, Union of
South Africa; and Mr. Emile Krieps , Minister of Health of
Luxembourg. Principal areas of interest to the visitors
were laboratory science, 54 visitors; administrators, 51;
medical science, 20; and medical educators, 18.
In November 1974, an eight-member pharmacology dele-
gation from the People's Republic of China visited NIH,
followed in May 1975 by the visit of an eleven-member
molecular biology delegation. Both delegations were spon-
sored by the National Academy of Sciences.
Another responsibility of the Visitors Center is
administrative management of the NIH Visiting Program, in
which international scientists participated during FY 1975.
Services included assistance with housing and other living
arrangements in the area, health insurance, income taxes,
visas, local educational facilities for dependents, pre-
paration and processing of appointment documents and ed-
ucational counseling for participants and other scientists
who are seeking career opportunities away from NIH. Analy-
sis of the program follows under a separate heading.
The Visitors Center also assisted 184 guest workers
from 42 nations at NIH during FY 1975 with many of the
same services rendered to scientists in the Visiting Program.
13
International Research Exchange Program
In Section 307 of the Health Services Research,
Health Statistics, and Medical Libraries Act of 1974,
Congress authorized the Public Health Service to parti-
cipate with other countries in cooperative endeavors in
biomedical research to "establish and maintain fellow-
ships in the United States and in participating foreign
countries." Under this legislation the Fogarty Inter-
national Center offers International Research Fellow-
ships and Senior International Fellowships. These fellow-
ships are offered in conjunction with the International
Research Exchange program, which evolved from an extension
to citizens of other countries (on September 16, 1957) of
the regular NIH Postdoctoral Research Fellowship program.
These fellowships were administered by the Division of
Research Grants until the international portion was trans-
ferred to the Office of International Research at NIH in
1961. In 1968 the newly established Fogarty International
Center assumed the administration of the International
Research Fellowship Program.
One thousand five hundred twenty-four new fellowships,
funded under the program from FY 1958 through FY 1975,
have provided opportunities for carefully selected highly
qualified foreign biomedical scientists to participate
in research under the tutelage of leading American scien-
tists. Each year applications from prospective fellows
are reviewed competitively for scientific merit by a panel
of experts convened at NIH. Applications are assigned
priority scores by the reviewers, fellowships awarded
according to this ranking, and the amount of funds appro-
priated for the program for that year.
International fellows have made significant contri-
butions to the research programs of their preceptors in
their host laboratories, thereby advancing the United
States capability for diagnosis, treatment, or prevention
of disease. The fellows bring different points of view
to research problems and sometimes introduce new and in-
novative methodology developed abroad. Typically, they
exhibit a high capacity for hard work and diligent devotion
to research as reflected in their active participation in
seminars and discussions and through their numerous pub-
lications in scientific literature. In FY 1975, 76 new
International Research Fellowships and 26 second-year
fellowships were awarded, at a total cost of $1,344,306.
In August 1974, with the establishment of the Senior
International Fellowship program, the program of NIH-spon-
sored fellowships became a two-way exchange. The senior
program enables carefully selected midcareer American
14
academic faculty members to work in the place of their
choice abroad. The purpose of the program is to increase
the interchange of ideas of mutual interest in basic or
clinical research and academic studies. It is intended
that the award will be a career-enhancing experience with
mutual benefit to the fellow and his foreign host. Awards
are made on the basis of scientific merit of the appli-
cation and the competition is keen. During FY 1975, 28
Senior International Fellowships were selected for award
from 45 applications. The funds expended for this pro-
gram amounted to $444,227.
Another portion of the International Research Exchange
program administered by the Fogarty International Center
is the group of fellowships offered to young American
postdoctoral scientists by the Swedish Medical Research
Council and the Swiss National Science Foundation. Each
year these two countries sponsor three fellowships each.
The Fogarty International Center advertises this - program
annually, sends out application kits, and reviews appli-
cations for the two sponsoring countries. The review
procedure is the same as for the International Research
Fellowships; the applications with their assigned priority
scores are forwarded to Sweden or Switzerland for final
selection of the fellows by the sponsor. Since 1964 the
Swedish Government has sponsored 28 American fellows; the
Swiss have sponsored 9 since their program was established
in 1973.
15
Visiting Program
Initiated in August 1950, this program sought the
participation and assistance of outstanding young scien-
tists for specialized research training as Visiting
Fellows and for substantive contributions to the progress
of NIH research as Visiting Associates and Visiting Scien-
tists. Many centers of scientific research in the United
States and abroad will benefit from the training and ex-
pertise acquired by these scientists in the NIH Visiting
Program.
The growth pattern of the program has continued at a
constantly accelerating rate. In FY 1965 there were 157
participants at a cost of $1.2 million; in FY 1970, 214
at $2.1 million; and FY 1974, 433 at $4.8 million. The
following table contrasts the two most recent years:
FY 1975
Visiting Fellows 302
Visiting Associates 121
Visiting Scientists 121
Total participants 544
Total countries 51
Total cost $6.5 mil.
In FY 1975, the following countries sent the most
scientists in the Visiting Program: Japan 117, India 64,
United Kingdom 43, Israel 38, Italy 31, and Taiwan 28.
In addition, NCI had the largest number of Visiting Pro-
gram participants with 133, followed by NIAMDD with 86.
Under this program, NIH bureaus, institutes, and
divisions invite scientists of their choice to participate
in one of the three program categories. In contrast to
Visiting Associates and Scientists, whose award is for the
performance of services for NIH, the Visiting Fellows' award
supports postdoctoral research training. Awards are made
to individuals with a doctoral degree in a health science
field whose postdoctoral experience does not exceed 3
years. The sponsor of the Visiting Fellow is expected to
provide educational opportunities similar to those pro-
vided by university faculty members to their postdoctoral
fellows .
FY 1974
231
106
96
433
47
$4.8 mi
1
16
Special Foreign Currency Program
The National Institutes of Health (NIH) Special
Foreign Currency Program, imprecisely referred to as
the "PL 480 program," enables NIH to participate in
collaborative research efforts of the international
biomedical research community and to utilize resources
of selected countries to further the attainment of the
domestic goals of the institutes and of the host
countries. This program brings the talents of U.S.
scientists and those from other countries to bear on
biomedical science and information exchange problems of
mutual interest. It is funded with currencies, designated
by the Department of the Treasury as excess to the immediate
needs of the U.S. that have primarily accrued under Public
Law 480 from the sale in past years of surplus agricultur-
al products. Thus, it neither contributes to the flow
of dollars abroad nor uses new tax revenues.
The collaborative character of the NIH program
requires that there be a scientist from NIH (intramural)
or a U.S. academic institution (extramural) as a partici-
pant. Research projects are selected by individual insti-
tutes on the basis of technical merit and potential
contribution to institute research objectives. Projects
are also subject to review within the host country for
technical merit and conformance with its national
priorities. The research activities are conducted under
formal agreements entered into by NIH, as an agency of the
United States, and the foreign government.
Funds for the Special Foreign Currency program are
derived from the appropriation for "Scientific Activities
Overseas," which for presentation purposes appeared in
the NIH appropriation for several years and was trans-
ferred to the Office of the Assistant Secretary for Health
(ASH) in FY 1975. The Office of International Health
of ASH/DHEW has responsibility for formulating policy
for administering the appropriation for the Special
Foreign Currency program. Funds are allotted to NIH on
the basis of conformance of projects to programs and
priorities of DHEW and priorities of foreign countries
negotiated by DHEW. The excess currency countries during
this fiscal year were Burma, Egypt, Guinea, India, Paki-
stan, Poland, and Tunisia.
The U.S. -owned currencies in Israel and Yugoslavia
have been reduced so that they are no longer "excess,"
and funds are no longer available in these countries for
new projects or continuation of previously supported
projects. This has severely curtailed the collaboration
with the biomedical science communities afforded by this
17
program. In an effort to attenuate the severity of the
financial impact and disruption of research programs
and to formally recognize the need for maintaining
collaboration, the Department of State has negotiated
bilateral agreements with the governments of Israel and
Yugoslavia through which remaining funds have been made
available during a phaseout period to provide time
in which to obtain replacement support. To avoid the
disruption of the scientific community experienced in
Israel and Yugoslavia, in the event of depletion of the
U.S. balance of Polish currency, the long-standing agree-
ment for health science cooperation with Poland has been
amended recently. During this fiscal year bilateral
agreements, which include a biomedical research component,
haye also been negotiated with Egypt and India. These
bilateral agreements establish policies, procedures, and
priority- areas of mutual interest to which the NIH
Special Foreign Currency program must conform. They
will have a significant impact upon the development
of the NIH SFC program and will become a major influence
on its character. A more detailed review of the five
agreements follows.
Israel
In FY 1968 it became apparent that balances of U.S.-
owned Israeli pounds were depleted to the point where funds
would no longer be available. The full impact of this
depletion was realized by NIH in FY 1973, when the first
projects reached the end of their previously committed
period of support and could not be continued.
In anticipation of this, the Department of State
and the Israeli government signed an agreement on
September 27, 1973, establishing the U.S. -Israel Binational
Science Foundation, to which each country contributed
equal amounts of Israeli pounds in a total equivalent to
$6 million. The income from the investment of these
funds provides for some new activities as well as the
continuation of projects and collaborations previously
established under the Special Foreign Currency program.
Approximately $2.1 million (equivalent) is available
annually from this source to all U..S. Government agencies
for the support of scientific and technological collabora-
tion.
Either U.S. or Israeli scientists may apply for
support, provided their requests represent collaborative
research efforts. Applications are submitted to the
Executive Director of the foundation in Jerusalem. The
foundation arranges for technical merit evaluation of all
applications, sending them to both U.S. and Israeli
scientists by mail. From the projects that have passed
this review, the Board of Governors of the foundation makes
the final selection for funding. The foundation operates
18
independently of NIH, with the exception that NIH is
requested to review projects to be funded for relevance
to NIH biomedical research programs.
Yugoslavia
In March 1972 an accounting revealed that the U.S.-
owned dinar holdings in Yugoslavia had been obligated
by the science and technology agencies to such an extent
that the currencies would no longer be in excess and that
a maximum of $7.2 million (equivalent) was available
for FY 1973 and FY 1974.
The Department of State negotiated the "agreement
between the Government of the United States of America
and the Government of the Socialist Federal Republic of
Yugoslavia on scientific and technological cooperation,"
which was signed on May 18, 1973, by the Director, Bureau
of International Scientific and Technological Affairs,
Department of State, on behalf of the United States, and
Mr. Krsto Bulajic, Director General, Federal Administration
for International Scientific, Education, Cultural, and
Technical Cooperation, on behalf of Yugoslavia. This
agreement established a joint fund for the support of
scientific and technological projects, including health,
and a U.S. -Yugoslav joint board on scientific and techno-
logical cooperation to administer the fund in the amount
of $14.4 million (equivalent) from equal dinar contribu-
tions by each country. At a meeting of the joint board
May 14-18, 1973, it was apparent that the income from
this fund would have little effect in moderating loss
of financial support; the decision was then made to commit
all the funds to provide limited support for projects
during a phaseout period of 3 years. NIH was allotted
funds for 24 projects. All active NIH projects in
Yugoslavia are now operating with financial support from
the joint fund.
The U.S. -Yugoslavia bilateral agreement has a unique
provision for matching U.S. dollar support of any former
NIH/SFCP or new research project of mutual interest on an
equal-share matching basis through the joint fund admini-
stered by the U.S. -Yugoslavia joint board on scientific
and technological cooperation.
Poland
A memorandum of understanding between the United
States and Poland, signed March 14, 1962, designated
NIH as the focus for development of a collaborative
research program in the biomedical sciences. NIH served
in this role until FY 1965 when in an effort to expand
the scope of the program by involving other DHEW
agencies, responsibility for administration and program
development was transferred to the Office of International
19
Health, at that time in the Office of the Surgeon General
of the Public Health Service and now in the Office of
the Assistant Secretary for Health.
On March 15, 1973, during the visit of the Minister
of Health of Poland, a revised memorandum of understanding
was signed by the Secretary of DHEW and Dr. Marian
Sliwinski, the Polish Minister of Health. For the
first time this agreement formally provided for the
exchange of scientists and the development of mutually
agreed-upon priorities and the annual review and revision
of these priorities.
On October 8, 1974, during the visit of Mr. Edward
Gierek, First Secretary of the Polish United Workers
Party, the health agreement of 1973 was revised and
raised to the status of a "country- to-country" agreement
and signed by the Secretary of State and Mr. Mieczyslaw
Jagielski, Deputy Prime Minister and Chairman of the
Planning Commission of Poland. This agreement included
two new provisions: establishment of a U.S. -Polish
joint committee for health cooperation and funding of
DHEW projects for the Marie-Sklodowska Curie Fund. This
joint fund was established by the agreement "Funding of
Cooperation in Science and Technology," which was also
signed at that time by the Secretary of State and
Minister Jagielski. This document, which also provided
for the establishment of a U.S. -Polish joint board, was
an implementation of the "science and technology coopera-
tion agreement" signed in October 1972 during the visit
to Poland of the President of the United States.
With the establishment of the joint board and the
joint fund, the Polish government has agreed to match the
sums that DHEW deposits for support of NIH and other
DHEW agency research projects. The administrative pro-
cedures incidental to operation of the fund are under
development. The joint board selected nine NIH projects
in the amount of $1,113,000 (equivalent) for support from
the joint fund. These concern the neurosciences and
immunologic and metabolic processes.
The priorities were given a second annual review at
a meeting of the joint board on U.S. -Polish medical coopera-
tion; it was agreed that those in effect during the past
year would be continued. It was also agreed that oncology,
which had been removed from the original list at the time
of the first annual review because of lack of activity,
would be reinstated as the result of recent developments
in this field. The current priorities are (1) occupational
and environmental health, (2) rehabilitation, (3) neurologic
and psychiatric diseases, (4) health problems related to
food and drugs, (5) infectious diseases and the immune
system, (6) planning, delivery, and evaluation of health
services, especially those to mothers and children, and
20
(7) oncology,
Egypt
An agreement on "principles of relations and coopera-
tion between Egypt and the United States" was signed by
Muhammed Anwar el-Sadat, President of the Arab Republic
of Egypt, and by the President of the United States on
June 14, 1974. The agreement established joint working
groups for Suez Canal reconstruction, trade and economic
growth, agriculture, technology, research and development
in science, and medical cooperation. The purpose of
the medical cooperation group, as stated in the agreement,
is "... to assist the Government of Egypt to develop
and strengthen its medical research, treatment, and
training facilities." The joint working group on medical
cooperation held its first meeting in Cairo October 28-
November 1, 1974, at which time priority areas for coopera-
tion were identified: (1) strengthening of health services,
(2) health manpower and medical education, (3) production
of pharmaceutical, biological, and medicinal products,
(4) environmental health, and (5) biomedical research.
During this meeting the delegates also prepared a prelimina-
ry delineation of the scope of each of the above priorities
for consideration and development in greater detail by
subsequent panels of expert consultants.
At the second meeting of the joint working group,
July 7-11, 1975, it was found that other subcommittees
for the aforementioned areas had subsequently assumed
responsibility for some aspects of the biomedical sciences.
The decision was made to appoint U.S. and Egyptian
representatives to give further consideration to the needs
of biomedical research in Egypt and, as appropriate, to
identify priorities to replace those developed previously.
India
An "agreement between the Government of the United
States of America and the Government of the Republic
of India to establish a joint commission on economic,
commercial, scientific, technological, educational, and
cultural cooperation" was signed on October 28, 1974,
by Secretary of State Kissinger and Mr. Y. B. Chavan,
Minister for External Affairs of the Republic of India.
The agreement provided for establishing subcommissions for
the fields of economic and commercial development,
scientific and technological cooperation, and education
and cultural cooperation. Health was included, with
industry and agriculture, as a responsibility of the
subcommission on science and technology. The first
meeting of this subcommission was held in Washington,
D.C., January 27-29, 1975, during which priority areas
were agreed upon as the basis for the program of coopera-
tion. During the development of these priorities by the
21
subcommission, a major objective of the Indian delegation,
comprised of representatives of the Ministry of Health
and the Indian Council of Medical Research, was to assure
that collaborative research efforts be directed toward
investigations of those aspects of problems of importance
to India. A further objective was the identification of
new or additional researchers and institutions with the
capability of carrying on productive research programs.
The priority areas agreed upon for collaboration in the
biomedical and health sciences are (1) communicable and
infectious diseases, with particular emphasis on prevention
and control techniques for such diseases as tuberculosis,
leprosy, malaria, filariasis, (2) reproductive biology
and fertility control, (3) health delivery systems for
efficient utilization of medical and paramedical manpower,
(4) nutritional, metabolic, and degenerative diseases,
(5) toxicologic research in naturally occurring toxins
in foods, pesticides, and drug residues, (6) other such
areas of biomedical and health science research as may be
proposed and agreed upon as being of mutual interest and
importance.
International Education Program
Applications for training 478 international health
professionals from 77 countries were processed during
FY 1975. Of these, 348 (73 percent) were for fellows from
the World Health Organization and other affiliated agencies
of the United Nations. Another 48 (10 percent) were for
participants in the Department of State Cultural Exchange
Program. The remaining 82 applications (17 percent) in-
cluded recipients of stipends from private foundations and
voluntary agencies (such as the Governmental Affairs Insti-
tute, the China Medical Board, the International Planned
Parenthood Federation, the Eisenhower Exchange Fellowships,
and the Institute of International Education) , as well as
those who were self-financed, sponsored by their governments,
or referred by other federal agencies. See Tables 1 and
2 for the distribution of such training programs, shown by
countries of origin (arranged according to WHO regions) and
fields of training.
In arranging, supervising, and evaluating the U.S.
training programs of international health professionals,
the branch staff has developed an extensive reservoir of
health training resources. Diligent efforts to expand these
resources have always been made to offer the widest choices
possible for combining individual potential and background
with the special needs of each country. One is cognizant
of the world's health problems by a glance at the types of
training requested: family planning, care of the aging,
water quality, solid waste disposal, drug abuse, venereal
disease control, air pollution, health care delivery and
22
economics, nutrition, migratory labor.
The branch is especially appreciative of the coop-
eration extended by the various institutes not only in
Bethesda but also in the field laboratories. The branch
continued its assistance to other federal agencies in the
field of health training.
The branch again provided assistance to the World
Health Organization in its selection of candidates from
the United States for short-term fellowships abroad. In
the interest of improving and expanding this country's
health services, these fellowships are made available to
selected U.S. citizens engaged in operational or educational
aspects of public health. Inquiries were received from
883 individuals, resulting in 92 applications. From these,
45 were chosen for fellowships by the selection committee.
Table 3 outlines the fields of training and states of
origin of those awarded fellowships.
23
Table 1
Countries Represented by International
Health Professionals, Applications Processed During
FY 1975
Sponsors
Country by WHO Region
WHO-UN
State
Other
Total
Region I : Americas
Argentina
Brazil
7
17
1
1
8
18
British Honduras
1
1
Canada
1
1
Caribbean Islands
36
36
Chile
5
2
7
Colombia
3
3
Ecuador
2
1
3
El Salvador
1
1
French Guiana
1
1
Guyana
Honduras
8
1
8
1
Jamaica
2
2
Mexico
10
•10
Uruguay
Venezuela
1
11
1
1
12
TOTAL
106
1
6
113
Region 2 : Europe
Algeria
Belgium
Czechoslovakia
1
1
3
1
1
2
3
Denmark
1
1
2
France
2
18
20
Germany (Fed. Rep.)
Hungary
Iceland
1
2
1
1
2
2
1
Ireland
2
2
Italy
Netherlands
2
10
6
16
2
Norway
Poland
16
2
1
3
16
Romania
4
4
Spain
Sweden
2
1
2
1
4
2
Switzerland
2
2
United Kingdom
5
1
6
24
WHO
Region
Sponsors
Country by
WHO -UN
State
Other
Total
Yugoslavia
1
1
2
TOTAL
45
34
13
92
Region 3 :
Africa
Ghana
1
1
2
Kenya
2
2
Lesotho
1
1
Liberia
6
6
Mauritius
1
1
Nigeria
1
1
Seychelles
1
1
Sierra Leone
2
2
South Africa
1
1
Uganda
1
1
Zambia
1
1
2
TOTAL
8
3
9
20
Region 4 :
Eastern Mediterranean
4
Afghanistar
t
3
7
Egypt
1
1
Ethiopia
4
1
5
Iran
6
1
7
Iraq
3
3
Israel
8
1
3
12
Jordan
1
1
Lebanon
3
3
Pakistan
5
1
6
Sudan
1
1
2
Tunisia
1
1
Yemen
2
2
Other
1
1
TOTAL
38
3
10
51
Region 5:
Southeast As
ia
Bangladesh
3
2
5
Burma
3
3
Ceylon (Sri
Lanka)
10
10
India
56
2
58
Indonesia
8
3
11
Nepal
2
2
Thailand
8
10
18
TOTAL
87
5
15
107
25
Sponsors ~~
Country by WHO Region WHO-UN State Other Total
Region 6: Western Pacific
Australia 4
Japan 1 1
Korea 10
Malaysia 7
New Zealand 3 1
Philippines 25
Singapore 9
Taiwan
Vietnam 2
Other 3
TOTAL .64 2 29 95
TOTAL ALL REGIONS 348 48 82 478
2
6
16
18
2
12
1
8
4
2
27
9
4
4
2
4
3
26
Table 2
Field of Training of International Health
Professionals, Applications Processed During
FY 1975
Sponsors
Field of Training
WHO-UN
State
Other
Total
Basic medical sciences
23
2
4
29
Behavioral sciences
10
2
1
13
Clinical medical sciences
33
4
1
38
Dentistry
6
1
-
7
Environmental health and
ecology
132
1
11
144
Nursing
14
2
7
23
Other biosciences
4
-
3
7
Other health-related
professional fields
Drug abuse
Epidemiology
Family planning
Health administration
Hospital administration
Pharmacy
Veterinary medicine
Mental health
Other
18
26
14
10
2
2
6
1
8
1
5
18
1
10
1
2
12
10
18
5
20
28
26
25
38
3
6
1
23
TOTAL
87_
35_
48
170
Paramedical technologies
Clinical
Environmental
Public health
2
1
13
-
2
1
4
1
14
TOTAL
16
_
3
19
Physical sciences
Sanitary Engineering
Statistics
Other
GRAND TOTAL
7
-
-
7
11
-
-
11
5
1
4
10
348
48
82
478
27
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28
Gorgas Memorial Institute
This institute was founded in 1921 as a living mem-
orial to Major General William Crawford Gorgas, whose
efforts in environmental sanitation led directly to the
successful construction of the Panama Canal and to the
virtual eradication of yellow fever from the great urban
centers of tropical America. With continuous direct sup-
port from Congress since 1929, the institute has operated
the Gorgas Memorial Laboratory in Panama City, Republic of
Panama. Support of the research and training activities
of the Gorgas laboratories comes from the Congressional
appropriation, philanthropic donations, and research grants
awarded by various agencies of the U.S. Government,
especially the Public Health Service and the Army. The
laboratories are one of the few research centers located
in a near tropical area that possesses modern facilities
and a well-trained staff. Another factor promoting the
laboratory activities is the fact that the Gorgas Institute
is an international organization capable of entering into
cooperative arrangements and studies with authorities and
investigators in any of the countries of the Western hemi-
sphere. Capitalizing on these characteristics the program
of the Gorgas laboratories has been devoted to research
investigations of human disease, training scientists in
tropical medicine, disease surveillance, and collaboration
in international health efforts.
From its inception, the laboratory has concentrated
its efforts toward the investigation and control of a
variety of infectious diseases of particular tropical sig-
nificance. Economic and social evolution has resulted in
changing disease patterns, which requires broadening the
scope of research activities of this laboratory. Thus, in
addition to studies of vectorborne disease, major emphasis
must be placed on enteric infections, nutritional derange-
ments , and other human health problems influenced by geo-
graphic, environmental, genetic, and social factors.
In 197 the Fogarty International Center assumed
responsibility for the congressional justification of
institute programs and, subsequently, encouraged a new
interest in scientific advisory activities relating to pro-
gram review and development. In 1972 the institute acquired
responsibility for the operation of the Middle America
Research Unit (MARU) a former field laboratory of the
National Institute for Allergy and Infectious Diseases
located in Ancon, Canal Zone. During its 16-year history,
MARU has gained wide international respect for its work
on such diseases as hemorrhagic fever, equine encephalitis,
and hepatitis of several Latin American countries. Al-
though MARU operations are now financed by annual contracts
with NIH, the Gorgas Memorial Institute has already effected
a consolidation of all its virological work at MARU.
29
Bilateral Agreements for Cooperation in Biomedical Research
In FY 1969, efforts were initiated to expand coop-
eration with other governments , involving biomedical
research. This new effort involved programs for collab-
oration within existing or newly negotiated bilateral
general science agreements. While deliberately drafted
to embrace a wide spectrum of scientific areas, these
programs encourage cooperating governments to share the
cost of research. Expenditures in the cooperating country
would be paid for by that government and those in the
United States by the American Government. Over the past
several years these arrangements provided additional
vehicles to utilize that reservoir of scientific and
technical biomedical personnel abroad who have contributed
to the advancement of the world's biomedical knowledge.
These bilateral agreements in science and technology
generally developed from a mutual desire to cooperate.
A visit to the country in question by a team of special-
ists representing science and technology usually initiated
the negotiation of the agreement.
Since these arrangements are very general in nature,
the Department of State usually designated one agency,
such as the National Science Foundation, of the United
States Government to act as overall "executive agency" in
coordinating implementation of these accords. If a
cooperative biomedical research project is developed by
a participating agency such as NIH under such a general
agreement, the project application is submitted to the
United States executive agency and its foreign counter-
part agency for approval.
To date, under the aegis of these governments, a
number of biomedical cooperative projects have been pro-
posed and several exchanges of information and personnel
have taken place between U.S. and foreign biomedical
laboratories. Although much informal collaboration con-
tinued on the scientist-to-scientist level in a large
number of the countries with which United States scientists
have contacts, formal cooperative activities in the bio-
medical and health sciences were limited to relatively
few. The countries involved in these general cooperative
agreements for FY 1975 were France, Italy, and Japan.
France
The U.S. -France Agreement for Scientific and
Technological Cooperation is administered by the U.S.
Department of State and the French Ministry of Foreign
Affairs. Many U.S. executive agencies participate in the
agreement. The National Institutes of Health collaborate
with their counterpart agency, the Institut National de
30
la Sante et de la Recherche Medicale (INSERM) on seven
research projects:
1. Biological, Immunological and Biomedical Studies
of Viruses Associated with Leukemia and Solid Tumors
U.S. Investigator: Dr. J. B. Moloney, NCI
French Investigator: Prof. G. Mathe , Hopital Paul
Broussee, Villejuif
2. Basic Reactions of Pulmonary Tissues to Inhaled
Pollutants
U.S. Investigator: Dr. Claude J. M. Lenfant, NHLI
French Investigator: Prof. P. Sadoul , Unite de
Recherches de Physiopathologie
Respiratoire , Nancy
3. Cellular Micro-Irradiation, Experimental Ultra-
structural
U.S. Investigator: Dr. W. N. Jensen, George Washington
University and Dr. G. Brecher,
University of Calif., San Fran.
French Investigator: Prof. M. Bessis, Institut de
Pathologie Cellulaire, Bicetre, Paris
4. Hormones and Cancer
U.S. Investigator: Dr. E. V. Jensen, Director, Ben
May Lab. for Cancer Res., Chicago
French Investigator: Prof. E. E. Beauiles, Hopital
de Bicetre , Paris
5. Myeloma Proteins
U.S. Investigator: Dr. Henry Metzger, NIAMDD
French Investigator: Prof. M. Seligman, Hopital
St . Louis , Paris
6. Perinatology and/or Pregnancy and Maternal Health
U.S. Investigator: Dr. Norman Kretchmer, NICHD
French Investigator: Prof. A. Minkowski, Cochin
Maternity Hospital, Paris:
P. Royer , Paris, and others
7. Thyroglobulin Synthesis
U.S. Investigator: Drs. J. E. Rail, J. Robbins and
J. Wiff, NIAMDD
French Investigator: Prof. S. Lissitzky, Faculte de
Medicine, Marseilles
31
Collaboration involves primarily exchanges of information.
However, three scientists from each side on each project
may spend up to 3 months in the other country's collabora-
ting project laboratories.
In the fall of 1974, when President Giscard D'Estaing
of France and President Ford met in Martinique, it was
agreed that cooperation in biomedical research should be
expanded. Subsequently, through a series of visits by
administrators on both sides, it was agreed to expand
cooperation, including the establishment of a strategy
committee for expanded cooperation in cancer research
beyond that already carried out under the agreement.
Following the visit to V. 7 ashington in June of 1975
by Mme. Simone Veil, the French Minister of Health, there
was an exchange of views between Secretary Weinberger and
Mme. Veil expressing joint support for the expansion of
U.S. and French cooperative activities in cancer research
through the INSERM-NIH agreement and giving approval to
the proposal for the creation of a Strategy Committee.
Italy
The United States-Italy Science Agreement, signed in
1967, is a general "umbrella" agreement for scientific
cooperation within which specific biomedical projects have
been incorporated since FY 1970. During FY 1975, as with
previous years, several ongoing and new projects were
recommended by the National Science Foundation to be
included within the above "umbrella" agreement. These
projects, the principal researchers, including those projects
now incorporated within the "umbrella" agreement and those
pending approval either by U.S. agencies or the Conseglio
Nazional delle Recherche are listed below under the
institute through which they derive support.
NCI
Immune Response of Mice Against Experimental Leukemia
U.S. Investigator: Dr. Gustavo Cudkowicz, State
University of N.Y.
Italian Investigator: Dr. Enzo Bonmassar, University
Of Naples
Characterization of the Viral Genome Products (RNA and
Proteins) Expressed by Cells Transformed by Mammalian
RNA Tumor Viruses
U.S. Investigator: Dr. Maurice Green, St. Louis U.
Italian Investigator: Dr. Giancarlo Vecchio, Uni-
versity of Naples
32
3. Antigenic and Chemical Characterization of Cells
Transformed by Adenoviruses
U.S. Investigator: Dr. Fred Rapp, Penn . State U.
Italian Investigator: Dr. Sergio Pauluzzi, University
of Peruzio
4. The Role of Cyclic Nucleotides, in the Regulation of
Gene Expression and Protein Synthesis in Animal Cells
U.S. Investigator: Dr. Ira Pastan, NIH
Italian Investigator: Dr. Stelio Varrone , University
of Naples
NHLI
1. Development of Physico-chemical Techniques of Bio-
logical Interest
U.S. Investigator: Dr. R. L. Berger, NHLI
Italian Investigator: Dr. L. Rossi-Bernardi , Univer-
sity of Milan
2. Basic Mechanisms Underlying Erythropoiesis
U.S. Investigator: Dr. Albert S. Gordon, New York
University
Italian Investigator: Dr. Cesare Peschle, University
of Naples
3. Relationship Between the Metabolism of Triglycerides
and Myocardial Function
U.S. Investigator: Dr. Marilyn E. Hess, University
of Penn.
Italian Investigator: Dr. Adalgisa Bizzi & Silvio
Garattini
4. Bioengineering Analysis of Microvascular Function
U.S. Investigator: Dr. Marcos Intaglietta, University
of Calif., San Diego
Italian Investigator: Dr. Rodolfo Monti, University
of Naples
5. Hemoglobin and Myoglobin Kinetic Studies
U.S. Investigator: Dr. J. Parkhurst, University of
Nebraska
Italian Investigator: Dr. Giuseppe Geraci , University
of Rome
33
6. Chemistry, Morphology, and Biological Activity of the
Pulmonary Surfactant System in the Fetus and Adult,
Normal and Abnormal
U.S. Investigator: Dr. Emile M. Scarpelli, Yeshiva
University
Italian Investigator: Dr. Ermelando Cosmi , University
of Rome
7. Patterns in Respiratory Control in Human Shock
U.S. Investigator: Dr. John H. Siegel, SONY
Italian Investigator: Dr. G. C. Castiglioni, CNR
8. New Modifications for Mechanical Ventricular Assis-
tance
U.S. Investigator: Dr. David B. Skinner, Johns
Hopkins University
Italian Investigator: Dr. Sergio Stipa, University
of Rome
NIAMDD
1. Biochemical and Genetic Studies on the Structure of
Histidyl-tRNA Synthetase and Methylation of Histidine-
tRNA
U.S. Investigator: Dr. Bruce N. Ames, University of
California, Berkeley
Italian Investigator: Prof. Francesco Salvatori and
Francesco de Lorenzo, University
of Naples
2 . Mechanisms of Glucose Transport and the Action of
Insulin
U.S. Investigator: Dr. Pedro Cuatrecasas , Johns
Hopkins University
Italian Investigator: Prof. Gennaro Illiano, Uni-
versity of Naples
3. Mechanism of Repression of Biosynthetic Pathways:
the Histidine Operon
U.S. Investigator: Dr. Robert F. Goldberger, NIH
Italian Investigator: Dr. G. B. Bruni , University
of Naples
4. Purification and Characterization of Human Glycosidases
and Study of their Possible Structural Alterations
in Sphinglipidoes
U.S. Investigator: Dr. Y. C. Lee, Johns Hopkins U.
Italian Investigator: Dr. G. Romeo, University of
Naples
34
5. Metabolic Effects of Acid-Base Disorders
U.S. Investigator: Dr. Arnold S. Relman, University
of Pennsylvania
Italian Investigator: Dr. A. Tizianello, University
of Genoa
NINCDS
1. Central Control of Neuromuscular Apparatus and Motor
Coordination
U.S. Investigator: Dr. Emilio Bizzi, MIT
Italian Investigator: Dr. Vincenzo Tagliasco, Uni-
versity of Genoa
Japan
During FY 1975 the U.S. -Japan Cooperative Science
Program, established in 1960 to foster a closer collabora-
tion between scientists of the two nations , included within
its program nine biomedical research projects listed
below :
1. The Development of Pharmacological Probes for Studying
the Cating Mechanism of Nerve Excitation
U.S. Investigator: Toshio Narahashi , Duke University
Medical Center
Japanese Investigator: Issei Seyama, Hiroshima
University School of Medicine
2. Reversible Interactions of Molecular Oxygen with
Cobalt Porphyrin Complexes and their Apohemoprotein
Complexes
U.S. Investigator: Takashi Yonetani, University of
Penn. and 3 others
Japanese Investigator: Takao Kwan , University of
Tokyo and 4 others
3 . Biomembrane Formation and Function in Tetrahymena
U.S. Investigator: Guy A. Thompson, University of
Texas - Austin
Japanese Investigator: Yoshinori Nozawa, Gifu Uni-
versity School of Medicine
4. Central Mechanisms of Motor Control
U.S. Investigator; Dr. Hiroshi Asanuma, Rockefeller
University
Japanese Investigator: Dr. H. Shimazu, University
of Tokyo
35
5. Development and Total Synthesis of Physiologically
Active Natural Products
U.S. Investigator: Dr. Lester A. Mitscher, Ohio State
University
Japanese Investigator: Dr. Tetsuji Kametani, Tohoku
University
6. Biochemical Studies on Biologically Active Complex
Carbohydrates
U.S. Investigator: Roger W. Jeanloz, Harvard University
Japanese Investigator: Tamio Yamakawa , University
of Tokyo
7 . Effects of Perinatal Exposure to Endocrine and
Oncogenic Factors
U.S. Investigator: Howard A. Bern, University of
Calif . , Berkeley
Japanese Investigator: Noboru Takasugi, Okayama
University
8. Amplification of Eukaryote DNA Fragments
U.S. Investigator: Bruce M. Alberts, Princeton
University
Japanese Investigator: Kenichi Matsubara , Kyushu
University
9. The Optical Properties and Structure of Deoxyribo-
nucleic Acid by Electric Dichroism Techniques
U.S. Investigator: Elliot Charney , NIH
Japanese Investigator: Kiwamu Yamaoka , Hiroshima
University
Geographic Health Studies
As suggested by the bilateral programs, the scientists
and science administrators of the National Institutes of
Health are actively seeking to expand their knowledge of
foreign health activities and programs to provide new
insights for improving the health of the American people.
Important elements of all health activities, of course,
include biomedical research, medical education, health
manpower and health services. An analysis of these foreign
health-related activities and programs may provide the
U.S. Government health administrators with new insights in
solving some of the complex problems relating to the
improvement of health in the United States.
Recognizing the cultural and other historical influence
upon foreign medical systems, no single country or govern-
ment may have the type of medical care or health system
36
which will provide completely adequate health assistance
desired by our citizens. A study of the best feature of
foreign health systems, however, ultimately may provide a
better understanding of the perspective within which health
exists in the United States. Such a perspective, however,
must include an improved comprehension of the political,
economic, social, and other cultural aspects of society
itself.
The Fogarty International Center, the first advanced
study center of its kind within the Federal Government,
therefore, is attempting to make information on the health
systems of other countries as widely available as possible
to both the pluralistic influences in the public and
private sectors affecting the decision making processes in
the United States. This information is also freely
available to the medical communities and governments of
other countries and international organizations. The
specific objectives of these studies are: 1) To advance
U.S. knowledge of health practices in different geographic
regions or individual countries of Europe, South America,
Asia, Africa and Australia; 2) To publish selected documents
covering all phases of medicine and health in these
different regions; and 3) To improve cooperation between
clinicians, health scientists, and health administrators
in the United States and other geographic areas .
The scope of the project may be divided into the
following areas. Biomedical research : 1) The overall
philosophy and organization of biomedical research; 2)
Research trends and priorities; 3) Objectives; 4) Resources
available; 5) Relationship to medical care. Interface
Between Research and Education and Training : 1) The
education of both professional and para-professional health
manpower in general; 2) The role of the medical school;
3) The effect of health care needs upon medical education;
4) The financing of medical education; 5) The influence of
public and private organizations upon medical school
curricula. Interface Between Research and The Delivery of
Medical Care : 1) The organization of health care systems;
2) Respective roles of public and private sectors in
improving health; 3) The economics of health; 4) Special
services to population groups such as mothers and children;
5) Geriatrics; 6) Mental health.
During FY 197 5 a number of publications were prepared
within the aegis of the Center's Geographic Health Studies:
Soviet Personalities in Biomediclne
This comprehensive volume, compiled in accordance
with an interagency agreement between the Fogarty Inter-
national Center and the Library of Congress, is considered
a most valuable tool in furtherance of contact between
American and Soviet biomedical research scientists. Listed
37
are 6,155 Soviet personalities associated with medicine
and health-related research, their date and place of birth,
education, specialization, career positions, professional
activities, honors and awards, publications and other
significant data. The personalities identified are those
considered most likely to be involved in exchanges in
fields of interest to the United States under the terms
of existing and future agreements.
Soviet Biomedical Institutions: A Directory
The companion volume to Soviet Pers o nalities in
Biomedicine (above) , this also was assembled by the
Library of Congress under the interagency agreement. Its
purpose is to provide United States biomedical scientists
with a guide to the organization, personnel, geographic
distribution, subordination, and research activities of
selected Soviet medical and biological institutions.
Described are some 1,200 institutions, including research,
education and service facilities, and learned societies.
Among the research facilities listed are institutes,
independent laboratories , and research and treatment centers
Health care facilities included are hospitals, polyclinics,
and dispensaries. Educational organizations listed include
medical training institutes, university faculties of
medicine and the military medical academy. Medical
societies on the All-Union level are also included. The
directory's detailed descriptions of Soviet facilities
are considered most important toward the exchange of in-
formation, personnel and delegations under the expanded
Agreement for Cooperation of 1972 and future agreements
of this type.
A Barefoot Doctor's Manual
Translated from the Chinese publication of like title
issued in September 1970 by the Institute of Medicine
of Hunan Province, this volume has been issued for limited
circulation in the United States. Its focus is upon
improvement of medical and health care facilities in rural
Chinese villages, with its primary purpose integration
of the following: prevention and treatment; disease and
symptoms, with stress on disease; traditional Chinese and
Western medicine; the native and foreign; mass production
and quality improvement. By delineating these principles
and addressing the actual conditions at the rural level,
the manual is aimed at meeting the working needs of the
sub-professional "barefoot doctors" serving the broad
rural population. Publication of this translated manual
is toward further investigation and a better understanding
of Chinese medicine and methods.
Soviet Research in Pharmacology and Toxicology
It is believed vitally important that workers in the
38
fields of pharmacology and toxicology be kept informed
upon drug studies being conducted in other countries, and
this publication is deemed valuable toward this end. The
author, Dr. William H. Fitzpatrick, having expert famil-
iarity with Soviet literature, has included 675 references,
and there is also a comprehensive index making the volume
an excellent reference text. It should prove of special
interest to those concerned with drug research and develop-
ment, in addition to those with a more general interest
in the subjects covered.
China Medicine As We Saw It
Recognized by reviewers as another step toward filling
in the spaces of the Chinese medical puzzle, this anthology
of personal reports by professionals is the first such
volume by recent visitors to the People's Republic of China.
Reported on in 15 chapters are Chinese innovations in
health; public health; its organization and status; public
health practices; prevalent diseases; and biomedical
research. Covered is a variety of subjects including:
traditional and modern medicine, limb reattachment,
acupuncture, fracture management, family planning, food
and nutrition, occupational health, and the special
significance of nasopharyngeal cancer in China. The volume
is illustrated, and has several tables and an index.
Chinese Herbal Medicine
The author of this work, Dr. C. P. Li, is a distin-
guished Chinese-born scientist, who also was responsible
for Anticancer Agents Recently Developed in the People's
Republic of China , published earlier by the Fogarty
International Center. Documented in this new volume are
the practices of the Chinese utilizing medicinal herbs,
resulting from an intensive study carried out by Dr. Li
with the approval of the People's Republic of China.
Included is an illustrated pharmacognosy of 44 individual
herbs discussed in the monograph. It is believed that this
work will prove helpful in further scientific investigation
and toward a fuller understanding of the subject.
A Bibliography of Chinese Sources on .'.Medicine., and
Public Health in the People's Republic of China:
1960-1970
This volume was also compiled by the Library of Congress
by means of an interagency agreement with the Fogarty
International Center. No fewer than 15,000 entries cover
articles in journals and newspapers, and monographs. These
are categorized under several headings including: acu-
puncture and moxibustion; allergy; anesthesiology; cardio-
vascular diseases; dentistry and oral surgery; dermatology;
endocrinology, metabolism and nutrition; gastroenterology;
hematology; infectious diseases; neurology; obstetrics and
39
gynecology; and 20 others.
Chinese Personalities in Biomedicine
The information contained in this publication was
also assembled by the Library of Congress under the inter-
agency agreement, using the same public sources as used
for the Bibliography of Chinese Sources on Medicine and
Public Health in the People's Republic of China: 1960-
1970 (above) . These sources comprise medical and related
journals published by the PRC. In addition to listing
the names of those prominent in Chinese biomedicine, the
volume also provides data on their education, appointments,
specializations, publications, memberships, and much other
pertinent information.
Acupuncture Anesthesia
This publication is a translation from the Chinese
volume of the same title, produced in November 1972 by a
Shanghai-based editorial and writing team at the request
of the Ministry of Public Health of the People's Republic
of China. Acupuncture anesthesia is a comparatively
recent development that has found increasing use and
success since the time of the Cultural Revolution. This
English-language version has been produced for limited
circulation to scholars having a general or specialized
interest in this aspect of health care.
Acupuncture Anesthesia in the People's Republic o f
China, 1973
Acupuncture anesthesia and therapeutic acupuncture
are subjects that since 1970 have piqued the interest of
the American public and the American medical profession.
This volume, written by Dr. James Y. P. Chen, a Chinese-
educated scientist-clinician with a distinguished American
background, is intended to provide Americans with an over-
view of acupuncture anesthesia. During a visit to the
PRC in 1973, Dr. Chen had opportunities to observe 30
operations performed under acupuncture anesthesia and to
discuss this and other aspects of health care with
numerous Chinese scientists, physicians, and other health
professionals. The publication covers many aspects,
including a summary of experience with this modality in
the West, the selection and preparation of patients,
selection of acupuncture points, application techniques,
and the intra-operative and post-operative management of
the patient.
Respiratory Research in the People's Republic of
China
The current state of knowledge of pulmonary medicine
reflects the contributions of scientists and physicians
40 -
working in many countries. The flow of information from
the People's Republic of China was interrupted for many
years, but it is now evident that there is much to learn
from Chinese pulmonary medicine. Many pulmonary diseases
are related to local ecology, and it is well known that
some aspects of physiologic function may differ among
ethnic groups. It is therefore considered fortunate that
Dr. Frederick F. Kao, eminent respiratory physiologist and
Professor of Physiology at State University of New York
undertook to study the contributions of Chinese research
in the field of respiration, and as a result prepared this
monograph reviewing the many facets of pulmonary research
and medicine in the PRC.
Urban Emergency Medical Service of the City of
Leningrad
Translated from the Russian work of M. A. Messel, this
publication discusses in detail the development and work
of emergency medical services in the USSR, with particular
emphasis upon the system prevailing in Leningrad. Described
are the operation of central and district stations, methods
of recording the stations' activities, the work of the
station physician, volume of medical aid rendered, and the
physician's tactics and operational methods. Also dealt
with are the prevention of accidents, and the role of the
station as an evacuation unit. The comprehensive volume
contains many illustrations and tables.
An Economic Analysis of the Cooperative Medical
Services in the People's Republic of China
The economics of cooperative medicine in the PRC
comprise the main theme of this monograph by Teh-wei Hu,
Visiting Research Professor at the Fogarty International
Center. Much light is thrown upon the manner in which,
in 8 years, the PRC established medical services relevant
to basic medical needs and an effective medical system.
The promotion of herbal medicine and the utilization of
"barefoot doctors" are described as cost minimization
approaches with great effect upon the economics of such
a medical system. The publication has relevance as a
study of interest for American specialists in the field
of public health and the provision of medical services.
The Center as a Coordinator for NIH International Activities
For a number of hears NIH has sought the collaboration
and scientific productivity of foreign scientists in ful-
filling its mission of improving the health of the people
of the United States and in contributing to the base of
scientific knowledge upon which American scientists depend.
The continuing limitation on the worlds resources, of
course, have accentuated the NIH intent to utilize out-
standing research opportunities regardless of geographic
41
location. Several different mechanisms are used to
maximize benefit from these international resources,
including grants and contracts to foreign institutions,
publication of biomedical data derived from reports from
abroad, and information from NIH participants in inter-
national scientific conferences and symposia. Thus, in
addition to its other programs discussed above, the
Fogarty International Center performs a coordinating role
in making available for use of the NIH scientific
community biomedical data derived through the aforementioned
and other mechanisms.
II
INTERNATIONAL COOPERATION IN THE HEALTH
SCIENCES BY COMPONENTS OF NIH
In addition to the activities in the international
health sciences coordinated by the Fogarty International
Center, many other components of NIH participate in
international programs, projects, and other activities
designed to promote the biomedical sciences. These
include cooperation with national and international
organizations throughout the world. The following
summaries of the more important aspects of these coopera-
tive efforts afford some measure of insight into these
activities.
43
NATIONAL CANCER INSTITUTE
Since the passage of the National Cancer Act in
1971, the international activities of the National
Cancer Institute (NCI) have been directed toward the
development of a more coordinated program of international
cooperation in cancer research and clinical care of the
cancer patient. The interrelationship that has been
established between the NCI and international institutions
and organizations certainly will be mutually beneficial
to all concerned, particularly since programs of inter-
national cooperation provide opportunities to immeasurably
broaden our understanding of cancer cause and cancer pre-
vention. For instance, variations in incidence rates
for different types of cancer throughout the world are
indicative of the role of geographic, social, and other
environmental factors in their development. Thus
"pooling" international efforts against cancer could more
rapidly result in the synthesis of a comprehensible whole
from those unique international components that might
otherwise continue in diverse directions for a much
longer period of time and with unnecessary expenditure of
economic resources. Perhaps the greatest benefit to NCI,
the national cancer program, and, ultimately, the cancer
patient, is the sharing of international cancer research
resources, particularly the resource of scientific intellect
and its product of meaningful information.
During FY 1975, the Office of International Affairs
within the Office of the Director, NCI, continued its
effort of implementing the programmatic goals set forth
in the act of 1971, as amended in 1974. A major effort
has been devoted to developing a cohesive method for
utilizing the cancer expertise that exists outside of the
United States. Emphasis has been placed on accumulating
all available data on cancer problems, analyzing that data,
and disseminating it throughout the world anticipatory
of such information serving as a data base for developing
a comprehensive international program of collaborative
cancer research.
International Cancer Research Data Bank
Program
Soon after the enactment of the National Cancer
Act, NCI established an International Cancer Research
Data Bank (ICRDB) Program. During its first 2 years of
activity the information needs of the cancer research
community were identified, existing information systems
described, and a scientific information system designed.
Ultimately, a detailed plan evolved for the operation of
this program.
45
46
Subsequently, a series of contracts were awarded for
its implementation. The contracts - the majority initiated
in FY 1975 - include efforts for (1) the rapid screening of
1,000 biomedical journals and other literature sources
for all articles related to cancer, (2) preparation
of abstracts of the cancer-related articles, (3) conversion
of abstracts to magnetic tape and related data-processing
operations required to produce and improve the ICRDB Data
Base, (4) collecting descriptions of currently active
cancer research projects from scientists located in
research centers around the world, and (5) technical
support to provide many special services needed by the
ICRDB program.
The more than 46 , 000 abstracts describing recent
results of cancer-related research and current cancer
research activities are made available with ease -to
scientists and clinicians through on-line computer termi-
nals located at more than 400 academic and research centers
throughout the United States and, increasingly, in other
countries. Using any combination of words or terms in
the title, text, or index field, scientists can retrieve
abstracts dealing with a specific cancer topic. The
entire text of the retrieved abstracts can be viewed at
a computer terminal or printed and mailed to the scientists.
The system, which uses the MEDLARS computer system of the
National Library of Medicine (NLM), is funded by an inter-
agency agreement between NCI and NLM.
Concurrent with literature screening and abstracting
is the collection and processing of approximately 10,000
brief descriptions of existent cancer research projects,
including short outlines of cancer therapy protocols.
This task is performed in the Current Cancer Research
Project Analysis Center (CCRESPAC) of the Smithsonian
Science Information Exchange, one of the ICRDB program
contractors. These abstracts are then made available for
on-line searching through the CANCERLINE network. In
addition, CCRESPAC will offer another information product
by producing some 30 technical bulletins listing current
research projects in specific narrow subject areas. The
bulletins will be distributed to scientists working on
the same specific topic in order to establish direct
communication with these colleagues.
At present, the ICRDB program is implementing and
operating four Cancer Information Dissemination and
Analysis Centers (CIDACs) . These receive inquiries
from comprehensive cancer centers, academic institutions,
private laboratories, individual researchers, clinicians,
and scientists throughout the world for the latest infor-
mation on a subject. CIDAC subject specialists query the
CANCERLINE data base, review the output, select relevant
abstracts, and forward the results of the search to the
user. This output includes not only the published litera-
47
ture available in CANCERLINE but also all ongoing research
projects in the data base.
CANCERLINE can be accessed on an "as-needed" basis
to respond to requests by the phone, mail, or personal
visit. Conversely, CIDACs will function as a
viable organization to stress the active dissemination of
cancer research information by automatically distributing
a steady stream of abstracts in specific subject areas
to scientists working in those areas as a part of a program
for the Selective Dissemination of Information (SDI) .
Current abstracts dealing with very narrow cancer subject
areas will be sent to researchers working in those areas
on a regular basis. Technical bulletins, each containing
abstracts covering several years of results in a specific
cancer research area, will also be published and forwarded
to users. The inquiries, as well as the current awareness
SDI products and technical bulletins, will all be obtained
by computer searches of the CANCERLINE data base.
Other current, active ICRDB projects include (1)
an International Registry of Tumor Immunotherapy
Protocols containing descriptions of over 200 clinical
trials of new immunotherapeutic procedures for treating
cancer; (2) an International Cancer Epidemiology Clearing-
house that is funded jointly by ICRDB, the International
Agency for Research on Cancer (IARC) in France, and
the German Cancer Research Center in Heidelberg; (3)
a contract with the International Union against Cancer
(UICC) for support of the Committee for International
Collaborative Activities (CICA) that promotes cooperation
between cancer centers around the world, serves as an
international advisory group for the NCI, and is assisting
in the development and dissemination of ICRDB program
products and services throughout the world; (4) a project
with UICC to collect data on cancer therapy protocols from
countries outside the United States; (5) the preparation
of a directory listing and describing more than 1,000
cancer research organizations in countries around the
world; (6) support of development of an improved
international classification of diseases (ICD-(0)) for
coding clinical cancer data under the auspices of the
World Health Organization; and (7) support of a new
program to collect information about cancer research
projects and results in Latin America.
COOPERATIVE RESEARCH
Cooperative cancer programs are in effect with a
number of foreign nations either as bilateral agreements
between governments or formal agreements between the
National Cancer Institute and a scientific institute or
society of a foreign country.
48
U.S.-U.S.S.R.
Established by the 23 May 1972 U.S.-U.S.S.R.
Agreement for Cooperation in the Fields of Medical
Science and Public Health, American-Soviet cooperation
is beginning to show dividends in almost all of the six
cancer problem areas agreed to for joint study.
1. Cancer Chemotherapy
During the Third Working Meeting of U.S.-U.S.S.R.
chemotherapists, April 1975, the status of clinical
and experimental studies on 49 American and 66 Soviet
drugs exchanged to date was examined. The results were
considered impressive, especially with the U.S. nitro-
soureas, hexylmethylmelamine, and DTIC; the Soviet's
ftorafur and asaley,- adriamycin from Italy; and the antra-
cycline antibiotics from both countries. U.S. use of asaley
and ftorafur, for example, has revealed preliminary clini-
cal efficacy of ftorafur against adenocarcinoma of the
gastrointestinal tract. Because of its decreased side
effects, ftorafur (an analog of 5-f luorouracil) may
prove to be effective clinically as a single therapeutic
agent or when used in combination with other anticancer
agents. Asaley is also showing some clinical promise, in
selected cancers.
Detailed analyses of these data will be the primary
content of a monograph, The Development of Drugs for
the Treatment of Cancer , being prepared jointly. This
monograph and another, Cancer of the Lung , are in final
review for publication.
Both sides are continuing patient accrual in joint
studies of lung cancer utilizing surgery with or without
CCNU as the modes of therapy, continuing studies of
epidermoid carcinoma, and undertaking pilot studies
jointly on the efficacy in small cell carcinoma of the
drug combination adriamycin-DTIC-vincristine.
Agreement was reached to organize a joint conference
on ovarian cancer to exchange generalized experiences of
both countries. It was agreed, as well, that for
experimental purposes one or two new , potential anticancer
drugs would be exchanged per year. There will be, in
addition, an active exchange of drugs of synthetic and
natural origin.
2. Cancer Immunology
During the second working meeting of U.S.-U.S.S.R.
immunotherapists, April 1975, the present status of
collaborative trials indicated that an impressive number
of patients have been entered into the trials. The
49
Soviet results, especially those combining chemotherapy
and immunotherapy, show considerable promise in the clini-
cal management of metastatic melanoma.
An important feature of this meeting was the agree-
ment to hold a conference on "Fetal and Tumor Antigens"
in the Soviet Union in 1975 to permit an intense exchange
of research information. This conference also provides
to many young Soviet scientists the opportunity for
active participation, as well as exposure to the most
recent advances being made by Americans working in the
broad interdisciplinary field of fundamental and applied
immunology.
3. Cancer Virology
In the third working meeting of the U.S.-U.S.S.R.
cancer virologists, May 1975, discussion focused on
the following results: (1) isolation of a group of
"potentially" oncogenic viruses from human cell lines in
continuous culture by both U.S. and U.S.S.R. scientists;
(2) isolation of "candidate" oncogenic viruses of the
herpes group and type C oncornaviruses from two species
of nonhuman primate inoculated with materials from
leukemic humans; and (3) isolation and study of a virus
associated with leukemia in cattle. These and other
findings were reported during a 2-day symposium entitled,
"Viral Neoplasia in Animals and Man."
4. Mammalian Somatic Cell Genetics Related
to Neoplasia
When this working group met for the second time in
June 1974, in Moscow, a symposium was held- "Mammalian
Somatic Cell Genetics Related to Neoplasia." Five
American and 11 Soviet papers were presented. Abstracts
of the papers have been published in Russian in the Soviet
journal, Genetika. A summary of the symposium will be
published in the Journal of the National Cancer Institute .
Although it was agreed then to continue the program of
cooperation as constituted during the first meeting, the
anticipated scientific momentum has not appeared yet.
5. Cancer Epidemiology
During the second working meeting convened in Febru-
ary 1975, two important agreements were reached as a re-
sult of the information exchanged: A monograph will be
published jointly on the current state of cancer epidemi-
ologic research in the United States and the Soviet
Union, and a joint study will be undertaken of the
epidemiology of cancer of the breast.
Acknowledging the invitation of the U.S.S.R.
50
coordinator, a delegation of American epidemiologists
spent October 5-18, 1975, in the Soviet Union exchanging
information with Soviet cancer epidemiologists and visiting
Soviet institutes engaged in cancer and cancer-related
epidemiologic research. The primary objective was the
design and development of a protocol for conducting
the joint project on the epidemiology of cancer of the
breast.
6. Cancer Control and Cancer Centers
Resulting from the second working meeting in Lenin-
grad in May 1975, there was agreement to pursue several
areas jointly: (1) the most effective means of early
detection of breast cancer; (2) objectives and methodology
essential to the rehabilitation of patients with breast
cancer; (3) efficacy of cancer therapy (end results)
using breast cancer as the model; and (4) the role of
U.S. cancer centers and Soviet oncologic institutes in
cancer control activities and their organization for
oncologic research, both fundamental and clinical. This
working group is expected to work in consonance with the
specialists in cancer epidemiology.
Interestingly, joint projects to study cancer of the
breast are included in five of the six problem areas,
genetics being excepted.
Scientist Exchange
Twenty-six Soviet cancer specialists visited the NCI
and other cancer centers in the United States for a
total of 23.30 man-months. Thirty-nine scientists from
the United States spent 20.20 man-months in visits and
exchanges in Soviet oncologic institutes.
NCI-Japan Society for the Promotion of Science
During the first year of the U.S. -Japan Cooperative
Cancer Research Program ten joint planning meetings and
scientific symposia were held in the areas of chemical
carcinogenesis, cancer virology, cancer immunology,
cancer therapy, analytic epidemiology, breast cancer,
lung cancer, bladder cancer, high-LET radiation therapy,
cytology, and metastasis.
Analytic Epidemiology
In July 1974 plans were made for Japanese epidemi-
ologists to work as exchange scientists in leading
American laboratories and for several of them to attend
NCI-sponsored meetings on national cancer programs to
obtain information on cancer epidemiology. In February
1975 discussions ensued concerning a mutual program in
51
approaching occupational data in respect to vaginal
and bladder cancer and the exchange of information and
comparison of data on the occurrence of childhood cancer
in Japan and the incidence rates in the United States.
In addition, special emphasis was placed on the desirabi-
lity of developing a Japanese counterpart of the U.S.
county maps for cancer mortality.
Lung Cancer
During visits to Japan, lung cancer specialists from
the United States were able to discuss the general
program on the treatment and control of lung cancer in
Japan and the most recent modalities of cancer chemotherapy,
They had an opportunity to visit research facilities and
to assess the clinical resources available for cooperative
programs in lung cancer. A planning meeting was held
on lung cancer morphology staging in order to develop a
unified system for the diagnosis and treatment of lung
cancer.
Breast Cancer
In July 1974 NCI-sponsored meetings enabled a delega-
tion of Japanese cancer specialists to observe the planning
and current programs of the Breast Cancer Task Force,
as well as to attend a scientific conference on estrogen
receptors. In February 1975 five Japanese cancer special-
ists participated in the Breast Cancer Task Force meeting
held in San Antonio, Texas. At a special meeting, the
Japanese group identified four areas for possible coopera-
tion: (1) early and/or minimal breast cancer; (2)
standardization and comparison of end results; (3) compa-
rative epidemiology; and (4) standardization of criteria
for evaluation of therapy. The Japanese Breast Cancer
Working Group has been reorganizing its program to
correspond to the organization of the NCI Breast Cancer
Task Force. Future plans were discussed for long-range
cooperation in these areas.
Cancer Therapy
A 3-day joint symposium was held on "Comparative
Study on Cytosine Arabinoside and Cyclocytidine" and
a workshop on the phase I study was held in Tokyo,
February 13-15, 1975. Five American scientists and 30
Japanese participated. Experimental and clinical studies
indicate that the American drug, cytosine arabinoside
(Ara-C) , is more effective than cyclocytidine (Japanese)
in acute myelocytic leukemia and less toxic. The use
of combination chemotherapy and combined modalities as
well as the possibilities of cooperative phase I studies
of new drugs were discussed.
A cooperative study on gastrointestinal tumors is
52
planned for December 1975 in Japan. A symposium on the
status of bleomycin and nitrosoureas in Japan and the
United States and surgical adjuvant approaches will be
proposed to be held in Hawaii, February 1976.
Bladder Cancer
The result of a planning meeting in Wisconsin,
February 1975, was general agreement that the Joint
U.S. -Japan workshop conference on "Experimental Models
for Bladder Cancer" be held in December 1975 during which
15-20 scientists from each country discuss and plan
cooperative research on experimental model systems.
In the spring of 1976, a workshop on the "Biochemical
Aspects of Bladder Cancer" is planned in Kyoto, Japan.
Tentative plans for meetings on pathology and treatment
of human bladder" cancer etiology, epidemiology of bladder
cancer, and bladder tumor-host response were made for
1976-1978.
Cytology
In February 1975 five American scientists visited
several research institutions and hospitals in Tokyo,
Osaka, Fukuoka, and Sapporo to observe ongoing research
in cytology, to review the state of the art of automated
cytology in Japan, and to explore areas for future col-
laborative research in cytology.
It was observed that the Japanese scientists, in
cooperation with several electronics firms, are developing
instruments for cytology automation using automatic
staining processes and cytologic scanners. The instruments
measure the nucleus size and shape, nuclear-cytoplasm
ratio, and nuclear density of the specimens. The instru-
mental developments are similar to those in the United
States. It was observed that more attention should be
placed on the preparation and standardization of specimens
for these studies.
Long-range objectives for cooperation should focus
on field testing and epidemiology, procedures for standard-
izing cytologic tests at the clinical level, information
exchanges on special techniques in cytology, investigative
cytology directed toward clinical application of cyto-
chemistry and immunocytology, and continued effort in the
development of cytology automation through the exchange
of research information, identification of individuals
engaged in cytology research, and the exchange of scienti-
fic personnel for information and collaborative research.
Cancer Immunology
The Joint Cancer Immunology Working Group held a
3-day meeting in Hawaii, March 1975, dealing with
53
"Immunotherapy of Cancer and Its Fundamental Basis."
Seventeen scientists discussed immunotherapy with BCG
and related material, immunopotentiators other than
BCG, immunotherapy with transfer factors or cells, immune
evaluation, and other types of immunotherapy.
Interest was expressed in clinical immunotherapy by
both sides. As a result it was tentatively agreed
that a second conference on cancer immunology be held
focusing on the problems and current research in
clinical use of immunotherapy.
Cancer Virology
The Joint Cancer Virology Working Group held a
symposium on "Recent Advances in Tumor Virology," March
1975, Hilo, Hawaii. The meeting, attended by 7 American
and 7 Japanese scientists, enabled the scientists to
familiarize themselves with ongoing research on RNA and
DNA viruses in each country. Discussions were held on
the exchange of experimental materials and information
and research areas for future collaboration. Plans are
now under way for a joint study of SV 40 mutants. A
second meeting on cancer virology is being planned for
spring 1976.
Chemical Carcinogenesis
A 3-day seminar, "Protease Inhibitors and Carcino-
genesis," took place in Honolulu, Hawaii, March 1975.
The seminar concentrated on the effect of a new group of
protease-inhibiting compounds, such as leupeptin, antipain,
and pepstatin, that exhibit an inhibiting effect on
experimental carcinogenesis. Information was exchanged
on the biochemical activity of these new compounds, as
well as other enzyme inhibitors.
The Japanese working group provided the Americans
with generous supplies of the protease inhibitors to be
distributed to American cancer researchers for their
investigations .
The chemical carcinogenesis groups have planned a
U. S.- Japan- Australia tripartite conference on "Modified
Cellular and Molecular Controls in Neoplasia" to be held
in Hawaii, December 1975. This large conference is being
sponsored by the National Science Foundation, the National
Cancer Institute, and the Japan Society for the Promotion
of Science (JSPS) .
High-LET Radiation Therapy
In July 1975 six American radiotherapists and
radiation physicists visited several radiation biology
and therapy centers in Japan for 7 days. Both joint
54
working groups discussed the various preclinical and
clinical aspects of neutron radiation therapy and reviewed
the availability of neutron beam therapy equipment, basic
radiation biology, and dosimetry. The joint working
groups, sponsored jointly by NCI and the JSPS, are now
working on the development of clinical trial protocols
for comparative studies.
Exchange of Scientists
Twenty-one JSPS-sponsored Japanese exchange scientists
visited from 2 weeks to 6 months the National Cancer
Institute and various American laboratories for conferences
and definitive collaborative research with American cancer
researchers. Five NCI-sponsored American scientists
visited Japanese institutions for 2 weeks to observe and
survey the development of the Automated Cytology and
Instrumentation Program. During April and May 1975,
an American scientist was engaged in collaborative
research in chemical carcinogenesis at the Institute of
Medical Science, Tokyo University.
U.S. -Polish Peoples Republic
Under the agreement between the United States
and the Polish Peoples Republic for cooperation in the
field of public health, NCI has established a working
relation with the Institute of Oncology in Warsaw.
In May 1975 an American exchange scientist visited
the Maria-Sklodowska Curie Memorial Institute of
Oncology in Warsaw and Krakow. During his stay this
individual presented lectures on the clinical aspects of
thyroid cancer, one of their continuing research efforts
over the years, and consulted with Polish scientists on
establishing a new therapeutic and research oncologic
center in Warsaw.
In June 1975 another American exchange scientist
visited Poland and presented a lecture on the "Progress
of Virological Studies in Cancer of Animals and Man"
at the Institute of Oncology in Warsaw. Seminars in
viral oncology and immunology were also conducted at the
branches of the Institute of Oncology in Gliwice,
Krakow, Wroclaw, and Poznan.
Potential Agreements with Other
Governments
In June 1975 a meeting was held between the director,
NCI, and members of his staff with Dr. P. Laudat,
Scientific Director for the National Institute of Health
and Medical Research (INSERM) , Republic of France .
Reference was made to the 1974 Martinique meeting
between Presidents Ford and Giscard d'Estaing. Dr. Laudat
55
summarized the interests of the two chiefs of state in
furthering American-French cooperation in health, especial-
ly in cancer research and cancer control activities.
The consensus was that a formal agreement was not necessary,
yet there was recognition of the need for expansion and
greater participation in the existing NIH-INSERM agreement.
Consequently, it was agreed to convene a small U.S. -French
strategy group to establish means for effective cooperation
that would include workshops on specific cancer problems
and the exchange of scientists, information, and research
materials .
In May 1975 the NCI director and members of his staff
met with a delegation of scientists from the Federal
Republic of Germany (FRG) , representing the Ministry of
Research and Technology, the Society of Radiation and
Environmental Research (Munich) , and the Cancer Research
Center (Heidelberg) . The purpose of the mission was to
express the interest by the FRG in developing agreements
for cooperation in research with specific U.S. agencies
(in this case, NCI). The areas of research appealing to
NCI and of particular interest to both the Ministry of
Research and Technology and the Society for Radiation and
Environmental Research are (1) instrumentation for early
diagnosis, including pattern recognition and isotope
scanning; (2) radiotherapy with high-energy particle
emission; and (3) testing plant extracts from the Amazon
region for clinical efficacy.
The NCI hosted the visits of two scientific delega-
tions from the People's Republic of China (PRC) ,
sponsored by the Committee for Scholarly Communication
under the aegis of the National Academy of Sciences. In
November 1974 six Chinese pharmacologists met with NCI
staff working in drug development, cancer chemotherapy,
and immunology. In May 1975 a delegation of biochemists
and molecular biologists from the People's Republic of
China were guests of the National Cancer Institute.
A meeting of the U. S. -Egyptian Joint Working Group
on Medical Cooperation was held in Washington, D.C., July
1975. There was an exchange of a draft agreement for
cooperation between the Ministry of Health of the Arab
Republic of Egypt and the Assistant Secretary for Health,
DHEW. The draft agreement is being considered by both
governments in anticipation of formal joint approval.
Collaborative Research
In accordance with established tradition, the National
Cancer Institute during FY 1975 has hosted visiting scien-
tists, associates, fellows, and guest workers from 29
countries, for collaborative cancer research projects with
senior NCI investigators. Of these 104 visitors, 20
came from Japan; 11 from India; 7 each from Israel,
56
Italy, and the United Kingdom; 5 each from Belgium,
China (Taiwan) , France, and Germany; and the remainder
from Argentina, Australia (2) , Canada (2) , Chile, Czecho-
slovakia, Egypt (2), Finland, Greece (2), Hong Kong,
Korea (2), Malaysia, The Netherlands (4), New Zealand,
Nigeria, Norway, The Philippines, Poland (2), Spain, Sweden
and Switzerland (3) . The scientists and their NCI hosts
engaged in fundamental research, environmental research,
clinical research, and cancer health services. There is
no question of the value of such scientist-to-scientist
interaction being the foundation for the development of
an eventual comprehensive program of international
cooperation in cancer research and research methodology.
Within the purview of the five operating divisions
of the National Cancer Institute, 26 grants and 91
contracts were in effect during FY 1975 in foreign
countries.
Under the provisions of Public Law 480, the Special
Foreign Currency Program, there are nine active cancer
research projects in four foreign countries (India,
Poland, Tunisia, and Yugoslavia) . The thrust of the
Yugoslav project is directed toward the study of immuno-
suppressive and antileukemic activity of pharmacologic
agents. Four of the Indian projects are related to chemo-
therapy, including the screening of indigenous herbal
substances as potential anticancer drugs.
To exemplify the benefit of this international
collaboration in cancer research, we relate to cancer of
the breast, which, at present, is one of the most frequent
cancers affecting women in industrialized countries.
Thus, under NCI contract the International Agency for
Research on Cancer (IARC) in Lyon, France, has organized
a special study of this problem in collaboration with
the University of Iceland. This study of the whole
population of Iceland has been initiated in an attempt to
measure the degree of risk that relatives of breast cancer
patients face of having breast cancer themselves. Such
a study is intended to compare the relative importance of
heredity and environment as risk factors in breast cancer.
Studies on cancer of the esophagus are continuing in
Iran, again, by the IARC under NCI contract. That this
cancer shows wide geographic variation in incidence both
between countries and between localized areas within a
country such as Iran raises the possibility of identifying
the causal factors. The detailed epidemiologic investi-
gation in this study has been completed and the data are
being analyzed. Preliminary results indicate a much
higher intake of bread in the high-incidence areas than in
the low-incidence areas where rice is the staple food. The
use of sheep's milk and sheep's milk yogurt was common
only in the areas of high incidence. No other foods
57
or vegetables showed any consistent relationship with the
cancer. Small amounts of carcinogens- both N-nitroso
compounds and polycyclic aromatic hydrocarbons- were
shown to be present in the food samples collected, but
the quantities seemed insufficient to explain the very
marked geographic variations. The project is continuing
with a case control study and with further chemical
analyses of food samples for known carcinogens, including
mycotoxins .
Liaison with International Agencies
Maintenance of an active association with internation-
al cancer research organizations is vital to NCI and the
national cancer program. The World Health Organization
(WHO) is an organization through whose auspices the
public health and medical professionals of more than
140 countries exchange their knowledge and experience on
health problems such as cancer. An integral part of
NCI's international activities is shared with other organi-
zations such as the International Union against Cancer
(UICC) , the International Agency for Research on Cancer
(IARC) , and the European Organization for Research on
Treatment of Cancer (EORTC) . The fruits of NCI's contri-
bution toward the support of these organizations and
agencies are evident from the progress being made in
the international arena where effort continues toward
achieving the highest possible level of health throughout
the world.
The registration of cancer morbidity on an interna-
tional scale is a prerequisite to studying the signifi-
cance of geographic variations and distribution. At
present, the IARC is collaborating with the International
Association of Cancer Registries to collect and publish
data under comparable conditions from different parts of
the world. The data are stored on magnetic tape in
the data-processing unit at WHO headquarters. The morbid-
ity data complement the mortality statistics routinely
collected by WHO. Since an internationally acceptable
and standardized classification of all forms of cancer
is essential for the systematic registration of cancer
mortality and morbidity, IARC has been involved in prepar-
ing the section on tumors for the next revision of the
International Classification of Diseases (ICD) , to be
published by WHO. Included in this revision as a voluntary
option will be a coding scheme for the histologic classi-
fication of tumors. This coding scheme is recognized to
be of increasing importance in cancer registration, and
will be especially valuable for identifying rare cancers
which might otherwise be lost in the registration system.
An inevitable feature of epidemiologic studies is the
long time taken for them to reach completion and publica-
tion. It is thus quite likely that during the period of
58
a given study, other workers with a similar interest may
start collecting similar data. While duplication in
epidemiology can provide valuable information, this will
only be so if the methods of collecting and analyzing
the data are comparable. It is therefore desirable to
establish some form of clearinghouse, from where
epidemiologists working in different countries could be
informed of studies in progress in an effort to avoid
unnecessary duplication and ensure that whatever dupli-
cation is needed will lead to results that are
comparable legitimately. Accordingly, IARC, in association
with the German Cancer Research Center, Heidelberg,
Federal Republic of Germany, has planned a clearinghouse
for current epidemiologic studies and related investiga-
tions in high-risk groups, including those subjected to
occupational exposures to potential carcinogens.
The coordination of studies in high-risk groups and
those subjected to occupational exposures will also
contribute to the work of the IARC in preparing its
monographs on the evaluation of carcinogenic risk of
chemicals to man.
The IARC is actively engaged in collecting, sifting,
and evaluating all published data relating to chemical
carcinogenicity testing and to epidemiologic studies
of the levels of human exposure to chemicals and, where
available, of their carcinogenic effects on man. The
program has resulted in the publication of IARC monographs
on the evaluation of carcinogenic risk of chemicals to
man. A total of 160 substances have been scrutinized and
the results are included in the six volumes already
published.
The selection of substances to be included in the
monographs conforms to two criteria. There must be evid-
dence of carcinogenicity of the substance in experimental
animals and evidence of human exposure to the substance.
The highest priority has been given to assessing those
substances for which carcinogenicity in man was suspected.
The preparatory work of selecting chemicals and collecting
information on them has been carried out in collaboration
with the NCI and the Stanford Research Institute.
Under NCI sponsorship, the Committee on International
Collaborative Activities (CICA) of the UICC is assisting
in the compilation of an International Directory of
Specialized Cancer Research and Treatment Establishments,
as a service to the international cancer research
community. A preliminary edition was compiled for
distribution during the International Cancer Congress in
Florence, Italy, October 1974. This directory will be
compiled now in a comprehensive edition and provisions
are included for regular updating. The directory
included information on comprehensive cancer centers,
59
cancer research institutes, university departments or
biomedical research centers engaged in a structured
program of cancer research, and hospitals or other medical
establishments having a separate but identifiable
organizational cancer department or unit. This project
is an integral segment of the ICRDB program, its source
of support.
NATIONAL HEART AND LUNG INSTITUTE
U.S.-U.S.S.R. Health Exchange
Cardiovascular Portion
The mutual interest in cardiovascular diseases stems
from a joint concern about the major threat that these
diseases pose to the health of mankind. Heart disease is
a health problem of great importance to the peoples of
many nations. It is the principal cause of death both in
the Soviet Union and in the United States. It has exten-
sive personal and social implications for large segments
of the population not only in terms of unexpected deaths
but also because it leads to chronic illness and loss of
work capability. The solutions to these problems repre-
sent difficult scientific challenges. Much more remains
to be learned in order to bring these diseases under con-
trol. Application of existing knowledge could also
decrease illness and death from cardiovascular diseases.
It is hoped that the U.S.-U.S.S.R. collaborative program
will accelerate progress toward these goals.
The U.S.-U.S.S.R. Joint Program in Cardiovascular
Diseases, one area included in the original 5-year agree-
ment between these governments, stresses that "the parties
agree to direct their initial joint efforts toward com-
bating the most widespread diseases, such as cardiovascu-
lar... diseases, because of the major threat that they pose
to man's health." A key element in this agreement that
was not included in earlier cooperative programs is the
mutual planning and execution of joint research activities
in both countries according to an organized work plan and
common protocols. A second important innovation is the
provision that the mutual cooperation take place directly
between specific U.S. and U.S.S.R. health institutions.
Thus, the National Heart and Lung Institute of the National
Institutes of Health was designated to collaborate with its
counterpart institution of the Soviet Academy of Medical
Sciences, the A. L. Myasnikov Institute of Cardiology in
Moscow.
The individuals responsible for organizing the ini-
tial efforts in the joint U.S.-U.S.S.R. cardiovascular
research programs were Dr. Theodore Cooper, now Assistant
Secretary for Health and then Director of the National
Heart and Lung Institute; Professor Eugene Chazov, Deputy
Minister of Health of the Soviet Union? and Professor Igor
Shkhvatsabaya, Director of the A. L. Myasnikov Institute
of Cardiology.
61
62
At its first meeting in 1972, the U.S.-U.S.S.R. joint
committee selected four programs for initial collaborative
efforts in cardiovascular diseases: pathogenesis of arte-
riosclerosis, management of ischemic heart disease, myo-
cardial metabolism, and congenital heart disease. Since
the 1972 agreement, further meetings of U.S. and U.S.S.R.
researchers have identified and agreed upon two new areas
for joint cardiovascular research: sudden death and blood
transfusion, blood components, and prevention of hepatitis,
with particular reference to cardiovascular surgery. In
addition, an artificial heart research and development
program is being developed under a separate agreement
signed June 28, 1974, in Moscow.
1. Pathogenesis of Atherosclerosis
Arteriosclerosis, the most common cause of cardio-
vascular disease, is directly or indirectly responsible
for more deaths in the United States and the Soviet Union
than any other disease. Because hyperlipidemia is strongly
suspected to be a major risk factor in causing premature
atherosclerosis and subsequent ischemic heart disease,
this subject area was chosen for joint study. Quantita-
tively, hyperlipidemia is perhaps the most important of
the known risk factors for arteriosclerosis. Not only is
extreme hyperlipidemia associated with high risk, but even
the "average" values believed to be present in American
and Soviet populations are associated with higher risks
than are the average levels in populations of several
other countries.
Automated techniques for classifying hyperlipidemia
according to standardized methods have been set up in a
number of lipid research clinics (LRC) in the United States
and Canada, supported by the National Heart and Lung In-
stitute. The major task of the current network of 12 lipid
research clinics is to collect data on the prevalence of
arteriosclerosis and information concerning environmental,
familial, and genetic influences. It is expected that new
standards of "normal" for lipids and lipoproteins for Amer-
ican populations will be set by this study. In addition,
an intervention trial is under way in the United States to
determine the beneficial effects of treatment of hyperli-
pidemia.
Through the U.S.-U.S.S.R. agreement this continentwide
study has been expanded to encompass an extensive compar-
ison of the nature and magnitude of the arteriosclerosis
problem in the United States and in the Soviet Union.
Combining the data from the U.S. clinics and the recently
established U.S.S.R. clinics will significantly broaden
the inferences and conclusions that can be drawn from the
study .
63
The U.S. -U.S.S.R. study which involves large numbers
of individuals (men, 40-59 years old) in the two countries
who are being studied according to carefully developed
common research protocols, intends to compare the preva-
lence of hyperlipidemia and ischemic heart disease in the
United States and the U.S.S.R. In the United States the
lipid research clinics program expects to study approx-
imately 22,000 individuals in the initial phase (phase 1)
of the study; and from 3,000 to 5,000 in the second, more
specialized, phase of the study (phase 2). In the U.S.S.R.,
the study is being conducted in Moscow and Leningrad.
10,000 individuals will be studied in phase 1 and
approximately 2,500 in phase 2.
This program has been the most active program in the
cardiovascular portion of the U.S. -U.S.S.R. health agree-
ment since its beginning. From the time of the signing
of the agreement on these studies, collaboration in this
area has been directed toward the achievement of standardi-
zation and unification of epidemiological and biochemical
methodology. During the past year significant progress
was made toward achieving these goals. In July 1974 a U.S.
delegation visited the Soviet Union to review the progress
in the cooperative study and the pretrials that had just
been completed in the clinics in Moscow and Leningrad and
to resolve any difficulties that may have arisen since the
last joint meeting. The delegation included five members
of the joint U. S. -U. S ,S .R. steering committee and five
members of the working group.
General issues on which agreement was reached included
a specific timetable with deadlines for each sequential
step leading to the formal study. U.S.S.R. representation
at meetings of the LRC directors and the U.S. Prevalence
Subcommittee was agreed to be desirable. Provisions were
made to improve the communications network and to transmit
data via telex until the Soviet computer system can be
developed and made operational. To institute regular
contact, it was agreed to exchange monthly reports.
In the biochemistry area, laboratory standardization
and quality control procedures were reviewed and clarified
where necessary. Tests for determining secondary causes
of hyperlipoproteinemia were discussed, and it was agreed
that each clinic would conduct its own tests, using
identical methodology, reagents, and standards. A certain
number of split samples would be exchanged by the two
laboratories to maintain comparability. In addition, the
Center for Disease Control, Atlanta, will provide quality
control pools and primary standards for secondary tests.
The epidemiology working group reviewed and defined
U.S.S.R. procedures for selecting the population sample.
In addition, significant discrepancies between the U.S.
64
and U.S.S.R. forms were discussed and amended. Plans
were made to initiate and test the exchange of study data.
Training and certification procedures for U.S.S.R.
dietitians were formalized. Four dietitians were cer-
tified during the visit. Agreement was reached on quality
control procedures for monitoring the coding of nutritional
data.
In the cardiology area, it was agreed that the U.S.S.R.
clinics would conduct the graded exercise test using the
treadmill. This will ensure comparability of cardiological
data. Agreement was also reached on the procedures for
conducting resting and stress ECG tests and for coding
ECG recordings.
Two Soviet scientists visited the United States in
November 1974 to attend the meetings of the Arterio-
sclerosis Council of the American Heart Association and
to represent the Soviet lipid research clinics at the
fall 1974 meeting of the U.S. lipid research clinic
directors in Dallas, Texas. Key items of the study were
discussed in biochemistry, nutrition, epidemiology, and
cardiology. A number of lingering problems in each area
were reviewed.
A U.S. working group visited the U.S.S.R. in March
1975 to finalize preparation for the formal U.S.S.R.
prevalence studies. At the time of the visit, the
Leningrad LRC was completing its pilot study, having
successfully passed laboratory standardization in January.
During the visit, the working group reviewed preliminary
pilot data from Leningrad and visit 1 screening procedures
at both clinics. It was confirmed that the Moscow lab-
oratory had passed the standardization program.
Training and certification of all interviewers is now
complete. ECG certification forms and tapes have been
completed in both clinics. The principal milestones in
the two Soviet lipid research clinics since the March
visit include (1) completion of pilot studies in both
clinics, (2) initiation of visit 1 of formal study, and
(3) initiation of visit 2 of formal study.
Two senior U.S.S.R. scientific workers visited the
United States in 1975 for 2 months. Their visits included
work at the laboratories of the Molecular Diseases Branch,
NHLI , and the Center for Disease Control. They also
attended the lipid research clinics directors' meetings in
Bethesda, as well as the meetings of the American Society
for Clinical Investigators in Atlantic City.
65
2. Management of Ischemic Heart Disease
While problem area 1 deals with the very important
subject of defining ischemic heart disease and its assoc-
iation with environmental and inherited factors in that
large portion of the populations in both countries who
are at risk of developing heart disease, problem area 2
is concerned with a second large segment of the- populations
in the U.S., U.S.S.R., and worldwide who are already
victims of the disease. This research is patient-oriented
and seeks to find ways to minimize mortality, morbidity,
and suffering.
In the United States, the surgical technique under
study uses a blood vessel graft to bypass a narrowed or
occluded segment of a coronary artery. Although over
25,000 such operations are done annually in the United
States for treating chronic disability from angina pec-
toris and heart attacks, the indications for and the
effects of coronary artery surgery in the treatment of
coronary heart disease remain to be determined. While
coronary artery surgery is very popular in the United
States, this method has received little following in
similar patient populations in the U.S.S.R. Conversely,
some of the medical approaches in the U.S.S.R. are un-
familiar to U.S. heart specialists.
Through the U.S. -U.S.S.R. agreement a collaborative
study is being developed that takes advantage of this
unique opportunity to systematically assess and compare
the way well-defined heart disease patients are treated in
the two countries. The ultimate goal of this coordinated
study is to assess various medical versus surgical ther-
apies for the treatment of ischemic heart disease. These
therapies include "differential" intensive medical manage-
ment in the U.S.S.R., "conventional" standardized medical
management in both countries, and coronary bypass surgery
in the United States.
Between 1972 and 1973, initial agreement was reached
on methodological bases of the U.S. -U.S.S.R. joint study,
such as the criteria for patient selection, patient ex-
amination, therapy, and assessing the effectiveness of
treatment. Pilot studies have been completed both in the
United States and the Soviet Union. Since then, U.S. and
U.S.S.R. cardiologists and cardiovascular surgeons have
met repeatedly to further define criteria for the selection
of patients who will receive differential medical treatment
and to develop specific work plans for the various phases
of the joint study. An exchange of fellows also took
place in 1973 and 1974.
66
Well-defined patients, that is, patients who both the
American and Soviet physicians are in complete agreement
concerning the state of their coronary artery diseases,
will be placed in one of three groups. Two "intensively
treated" groups and one "reference" group, will be com-
posed of men, 30 to 60 years of age.
In the United States, patients who have one or more
coronary arteries occluded by lesions causing greater
than 70 percent obstruction will be treated surgically.
In the Soviet Union, the method of treatment for patients
with identical heart disease will be entirely nonsurgical.
It will consist of a combined drug therapy and exercise
program carried on in the hospital and, after discharge,
in a health resort.
It is anticipated that the end points for the joint
study will occur in 5-8 years. Two years are required
for patient intake. A subsequent 5 year follow-up period
plus 1 year for data analysis is anticipated. During the
5-year follow-up period the patients in the U.S . -U.S.S.R.
international study will be examined periodically to
evaluate the effectiveness of their respective therapies.
From May 26 to June 7, 1974, a U.S. delegation visited
the U.S.S.R. to review the progress and to develop
further plans for the upcoming year. The overall study
design and the protocol of February 1973 were reviewed
in detail. Specific task forces also met on angiography
and electrocardiography. Although modifications in the
detailed protocol were largely clarifications, some
specific modifications - such as the elimination of the
requirement for a specific number of anginal attacks per
week, angiographic and ventriculographic characterization
of patients in the intensively managed group, elimination
of the requirement that the conventional medical management
include only the intermittent use of such agents as long-
acting nitrates and propranolol, and a decrease in the
frequency of required follow-up - were advanced. A mem-
orandum of understanding was drawn up, detailing the
future plans of collaboration.
A reciprocal visit by a Soviet delegation to the United
States, October 25 through November 7, 1974, enabled
scientists to review experiences in the pilot studies in
the Soviet Union and in the United States, to further
clarify plans and protocols, and to develop plans for the
future. Based on experiences of the domestic studies in
each of the two countries and the international U.S.-U.S.S.l
plans, all of which were in advance development stages,
opportunities for improvements in each of these plans
became evident. In addition, record forms were exchanged
that will serve not only to develop the international
U.S. -U.S.S.R. study, but to aid each of the two domestic
67
studies in their future development. Particular attention
was paid to the analysis of coronary angiograms, review of
electrocardiograms, and patient follow-up.
Since the October 1974 joint meeting, communication
has been maintained between the U.S.-U.S.S.R. coordinators
in order to complete collaborative plans in a timely
fashion. In May 197 5 the U.S. coordinator forwarded
information to the U.S.S.R. on the pilot phase of the U.S.
studies, as well as an extensive document containing the
plans for the definitive U.S. study. These plans had just
been reviewed by a U.S. advisory group at that time and
formally approved by the National Heart and Lung Institute.
In preparation for the September 21 - October 3, 1975,
U.S.S.R. visit by a U.S. delegation, the United States
has prepared copies of angiograms for joint viewing to
further U.S. and U.S.S.R. standardization of angiographic
interpretation. Also, a computer program that will print
out the data from the domestic U.S. study in the sequence
of the U.S.-U.S.S.R. international study is being developed.
It is expected that results of this effort will be available
for the September meeting.
3. Myocardial Metabolism
A fundamental understanding of the structure and
function of the heart muscle is crucial to the development
of improved methods of prevention and therapy for heart
disease. Specifically, it is important to search for
therapies that will enable the heart muscle to survive
a heart attack and to develop methods that may prevent
additional heart muscle damage.
The role that this research project will play in
future cardiovascular programs is likely to be a very
important one, both in terms of joint development of new
therapies and methods of prevention. Research areas
currently being addressed by Soviet and American scientists
include the manner in which heart muscle cells obtain
energy, regulate their growth, coordinate their contrac-
tions, and respond to induced alterations in their envir-
onment. These studies entail basic exploration at the
most sophisticated levels of modern medical science, in-
cluding physiology, molecular biology, biochemistry, and
biophysics .
Because of this inherent complexity and specialization,
it is difficult to identify areas where major collaborative
research projects can be carried out in the immediate
future. However, the regular and constant reporting of
research results and the exchange of technical information
68
can be of invaluable assistance to researchers in the
United States and the U.S.S.R. in their common goal to
prevent and control heart disease. To accelerate this
exchange of information, under the joint exchange agree-
ment, a symposium was held in the United States in
November 1973. Extensive discussion of many different
research projects relating to myocardial metabolism led
to the identification of new leads and ideas that will
serve as the basis for future collaborative efforts.
Significant advances in the understanding of myocardial
metabolism were identified, which demonstrated the high
level at which this research is conducted both in the
United States and the Soviet Union.
The proceedings of the symposium have been published
in English as a supplement of the journal Circulation
Research . The proceedings have also been published in
Russian in the Soviet Union. Arrangements have been
made for the regular exchange of important research reports
for mutual publication on a regular basis. Professor
Chazov's book, Myocardial Infarction , has been translated
into English under the auspices of the National Library
of Medicine and the National Heart and Lung Institute and
will be published in the United States in the near future.
Three U.S. exchange fellows spent extended periods of
time working in Soviet laboratories in the area of myo-
cardial metabolism. Dr. Rannels and Dr. Shell worked
mainly in the myocardial research laboratories at the
Myasnikov Institute of Cardiology in Moscow, but visited
cardiovascular institutes in other Soviet cities as well.
In the spring of 1975, Dr. Muller from the Department
of Medicine, Harvard Medical School, spent 3 months in the
U.S.S.R. His project was an intensive joint U.S.-U.S.S .R.
clinical study of the effect of hyaluronidase on reducing
infarct size in man. Although complete analysis of the
data of this study has not been made, preliminary analysis
appears to support the hypothesis that hyaluronidase treat-
ment reduces infarct size.
Dr. Saks, senior scientific worker at the Myasnikov
Institute of Cardiology, visited the United States as a
Soviet fellow in the spring of 1975. His program included
visits to the Laboratory of Cell Biology, National Heart
and Lung Institute; the Johnson Research Foundation at
the University of Pennsylvania in Philadelphia; the
Milton S. Hershey Medical Center, Pennsylvania State Uni-
versity; Johns Hopkins School of Medicine; the Cardio-
vascular Research Laboratory, UCLA Medical Center in Los
Angeles; and the Department of Physiology, University of
California at Berkeley. In addition he attended several
scientific meetings. Dr. Saks, and one of the U.S.
exchange fellows, Dr. Shell, have completed a research
69
paper as a result of their collaborative research in Moscow;
the paper, "Studies of Mechanisms of Energy Transport in
Heart Cells", will be published in Circulation Research
in 1975.
In June 1975 a second Joint Symposium on Myocardial
Metabolism was held in the Soviet Union to promote further
exchange of the latest information in this important
area of research. During the joint discussions in
Sochi, both sides agreed that as a result of the U.S.-
U.S.S.R. collaborative efforts initiated following the
1973 U. S.-U.S. S.R. symposium in Ponte Vedra, particularly
the exchange of young scientists from both countries,
important new lines of joint research have been outlined
of potential benefit to the people of the United States
and of the Soviet Union. The following studies were
completed or are in progress: clinical studies aimed at
limiting the extent of damage to heart muscle following
myocardial infarction, studies of the regulation of protein
synthesis and degradation in the myocardium, studies of
energy transport in the myocardium, and properties of
creatine phosphokinase from heart muscle.
The topics discussed included disturbance in the
function of the heart muscle in patients with ischemic
heart disease, the effect of hormones and drugs on normal
and ischemic heart muscle, changes in the blood circulation
to the heart during ischemia, energy processes in the heart
muscle, and possible clinical applications of the results
of these basic studies. The proceedings of the symposium
will be published in Russian in the Soviet Union and in
English in the United States.
4. Congenital Heart Disease
Congenital heart disease is an important disease of
children and young adults, both in the United States and
in the Soviet Union. In the United States, about eight
of every 1,000 children are born with this disease.
There are many types of congenital heart defects.
Each may occur alone, or in combination. Less than 3
percent are known to be related to a particular event or
disorder occurring during pregnancy, such as rubella
infection, or the use of certain drugs. Thus, in the great
majority of cases congenital heart disease cannot as yet
be prevented and, therefore, the only hope for these
children is therapeutic measures to correct or control
their heart disease.
Congenital heart disease may cause considerable im-
pairment of the quality of life of the patient surviving
70
into adulthood. Fortunately, approximately 80 percent of
infants with this disease can now be cured or helped with
corrective surgery. These surgical successes are now being
expanded by the development of diagnostic and surgical
techniques applicable to the newborn.
The objectives of the U.S . -U.S .S .R. collaboration in
this research area are to explore new methods of diagnosis
and postoperative care in order to further reduce mortality
from congenital heart disease and to improve the surgical
treatment of complex heart defects. It is hoped that
through the exchange of information in this problem area,
Soviet and American surgeons will be able to achieve a
higher rate of success in corrective surgery of congenital
heart defects. The proceedings of the second joint sym-
posium will be published by the Soviets in both English
and in Russian. It is expected to be published in the
first quarter of 1976. The United States was responsible
for the editorial review of the English version of the
proceedings. The proceedings will be distributed to
the U.S. and U.S.S.R. participants and all interested
scientists .
5. Sudden Death
Fifty percent of all deaths from coronary heart
disease occur suddenly. Sudden death coronary arterio-
sclerosis may occur in individuals with no symptoms of
heart disease, in patients with angina pectoris, in
patients with a history of heart attacks, and during an
acute heart attack. The immediate mechanism of sudden
death is believed to be a disturbance in the rhythm of
the heart.
The topic of sudden cardiac death is of major concern
to scientists in the United States. A series of studies
have been undertaken to identify factors that precipitate,
or "trigger", acute heart attacks in patients with coronary
arteriosclerosis. It is hoped that these studies will
help to elucidate factors in the person or his environment
that make him highly susceptible to potentially lethal
heart attacks and to discover premonitory signs and sym-
toms that may warn the patient or his physician of an
impending attack in time to take preventive measures or
to hospitalize the patient before the onset. Other studies
have involved the identification of factors that cause or
contribute to a quickly fatal outcome after onset and the
development of practical methods for treatment of the
very early stages of the acute heart attack in an effort
to lessen the risk of sudden death.
The avoidance of sudden death from cardiac arrhythmia
is a very important area of study for any collaborative
71
efforts to reduce coronary heart disease mortality. Soviet
and American physicians alike are looking for effective
ways to deal with the problem.
The area of sudden death was one of the new cardio-
vascular program areas approved under the official agree-
ment at the annual meeting of the Joint U.S .-U.S .S.R.
Committee for Health Cooperation in 1973. A. U.S. dele-
gation visited the Soviet Union in the fall of 1973 to
discuss the development of initial plans for collaboration
in this area. Soviet and American scientists exchanged
information and held extensive discussions on the follow-
ing topics: the magnitude of the sudden death problem in
both countries, risk factors for sudden death, the rela-
tionship between arrhythmias and sudden death, current
approaches to management of sudden death in the United
States and the Soviet Union, emergency treatment that
might be useful in controlling arrhythmias, suggestions
for joint U.S .-U.S .S .R. projects, and the development of
mechanisms for ongoing exchange.
In contrast to problem areas 1 and 2 , at the initia-
tion of this area of collaboration, there were no current
or projected large-scale collaborative activities in
either the United States or the Soviet Union. A number
of pilot studies were in progress in the United States.
The immediate task of both the United States and the
Soviet Union was to rapidly assess the current state of
the art and to form interested and competent working groups
to explore current activities and future opportunities
for joint research in sudden death.
U.S. scientists interested in and working in the area
of sudden death met in the fall to exchange current infor-
mation on the relationship between arrhythmias of the
heart and sudden death. The proceedings of this meeting
will be published shortly and will be made available to
the Soviet scientists in problem area 5. Also in the
fall of 1974 the National Heart and Lung Institute, in
collaboration with the Division of Computer Research and
Technology, sponsored a conference on computers in cardi-
ology. The topics discussed during this conference have
direct relevance to this problem area, and the proceedings
of the conference have been forwarded to the Soviet
scientists engaged in the U.S .-U.S .S .R. collaborative
activities in sudden death.
To move ahead in this area, the United States has
provided U.S. S.R. scientists with monitoring equipment
for the joint study. Shortly after the third joint
committee meeting, the U.S. S.R. reported that four Soviet
physicians had already been trained to operate the equip-
ment. However, Professor Lukomsky ' s untimely death post-
72
poned any possible expansion of collaborative activities,
and the U.S.S.R. has requested a delay in initiating the
collaborative effort. In January 1975, the Soviets
reported having difficulty with the monitoring equipment
provided by the United States and requested U.S. assis-
tance in analyzing the problem. A series of magnetic
tapes were forwarded to the U.S. coordinator for analysis.
A U.S. delegation visited the U.S.S.R. in June 1975
to review program plans and to develop a plan for the
upcoming U.S. visit by a Soviet delegation. The major
discussions of activities in this problem area were held
at the Myasnikov Institute of Cardiology. The delegation
also visited the Institute of Cardiology in Tbilisi. The
Soviets have made a definite new commitment in the area
of joint work on sudden cardiac death. A decision has
been made to expand joint collaboration with the Myasnikov
Institute to involve cardiology institutes in Kaunas,
Lithuania, and Tbilisi, Georgia, thus moving the collab-
oration toward a truly national Soviet effort in this
problem area.
The U.S. coordinator presented an overview of sudden
cardiac death studies in the United States. Like the
United States, the U.S.S.R. is also pursuing two main
directions of research in sudden death: basic studies
of sudden death and public health programs aimed at
identifying the population at risk.
Some of the most recent work in the area of sudden
cardiac death in the United States has been detailed,
such as determination of the prevalence of ectopic activity
in the population and qualitative and quantitative rela-
tionship of this ectopic activity to the major risk factors
being studied in the multiple risk factor intervention
trial population.
During its visit, the U.S. delegation was informed
by the U.S.S.R. scientists that there had been considerable
delay in initiating the joint studies with the monitoring
equipment provided by the U.S. Apparently, the Myasnikov
Institute where the studies were to have been performed
had been closed for about a year. It was only in January
1975 that the 24-hour monitoring study could be started.
The current studies are on patients who have had a myo-
cardial infarction, conducted in accordance with the pro-
tocol previously agreed upon in joint discussions with the
United States. The purpose of task 1 is to determine the
prevalence of arrhythmias in patients and the relationship
to sudden death. This task is being implemented. Task 2
on the U.S.S.R. side will be concerned with the epidemio-
logy of sudden death. It will be conducted in healthy
people, in people with risk factors, and in people with
73
ischemic heart disease. The purpose of task 2 is to
determine the correlation and identify specific conditions
for increased trends of sudden death. U.S. monitors
and analyzers will be used only for task 1.
The current plan for U.S.S.R. task 1 is for the
Myasnikov Institute to monitor 400 patients a year for
3 years and for the cardiology institutes in Tbilisi and
Kaunas to monitor 100 patients a year each. These patients
will also be monitored for 3 years.
The U.S. coordinator met with the Myasnikov staff
directly involved in the monitoring study to review
accumulated data. He also reviewed in detail the U.S.S.R.
magnetic tapes submitted to the U.S. for analysis. Detailed
reports were left with the Soviet scientists for their
study and comparison.
The U.S.S.R. is continuing the study of the relation
of ventricular ectopic activity to risk of sudden death
in patients with ischemic heart disease, using the equip-
ment provided by the U.S. for monitoring and analyzing
the data. U.S. scientists have agreed to provide technical
consultation as needed.
U.S.S.R. and U.S. scientists are also proceeding as
planned with studies of frequency of different types of
ventricular ectopic activity in selected high-risk pop-
ulations and in the general population and have agreed
to exchange results from these studies.
6. Blood Transfusions, Blood Components, and the
Prevention of Hepatitis in Cardiovascular Surgery
The past two decades have witnessed rapid advances
in the use of blood for therapeutic purposes. High-quality
blood and blood products are essential for the effective
treatment of many diseases. To give the patient enough
of what he needs and when he needs it requires recruiting
donors, collecting the blood, separating it into its
components, detecting and eliminating disease-causing
agents, matching the components for compatability , and
administering the blood to the patient in a failsafe manner.
The problem of blood transfusion, blood components
and prevention of hepatitis, with particular reference to
cardiovascular surgery, was approved as a new problem area
in 1973, at the joint U.S .-U.S.S .R. committee meeting.
The problem area not only provides a link between our two
countries in an area of mutual interest and needs, but it
also promotes the collaboration of internists and surgeons
who may view the problems of blood management from dif-
ferent perspectives.
74
A U.S. delegation made a preliminary visit to the
U.S.S.R. in December 1973; a reciprocal visit by a Soviet
delegation was made to the U.S. in October 1974. The
U.S.S.R. delegation visited many important blood centers
and laboratories in the United States: The New York
Blood Center, the International Hemophilia Training Center
at Mt. Sinai Hospital in New York, the Ortho Diagnostics'
research laboratories and production facilities in Raritan,
the NIH Clinical Center Blood Bank, laboratories at the
Bureau of Biologies of the Food and Drug Administration,
and the American Red Cross.
The second joint U. S. -U. S . S . R. working meeting in
this problem area was held at the National Institutes of
Health, October 21-23, 1974.
The delegation adopted two major themes for colla-
borative scientific investigations: approaches to the
prevention of hepatitis in blood transfusion, particularly
in cardiovascular surgery and the use of whole blood,
blood components, blood derivatives, and blood and plasma
substitutes with particular emphasis on cardiovascular
surgery.
To approach this collaborative effort in a well-
organized manner, the U.S. and U.S.S.R. coordinators
exchanged in January 1975 lists of principal centers in
each country engaged in research in the identified subject
areas. In March 1975 the coordinators exchanged preliminary
plans for implementing projects in the two major themes.
Discussions of these preliminary plans will be held during
the September 1975 U.S.S.R. visit of a U.S. delegation.
The key element in the development of these joint projects
is the exchange of young health specialists who will
actively participate in evolving the program. It is
anticipated that the first exchange of U.S. and U.S.S.R.
health specialists in this area will begin at the end
of 1975 or early 1976.
Artificial Heart Research and Development
In June 1974 after 2 years of exploratory discussions
and exchanges, the governments of the U.S. and the U.S.S.R.
signed an agreement designating the field of artificial
heart research as a new area of cooperation. The U.S.-
U.S.S.R. agreement in artificial heart research and
development provides for joint efforts in research on,
and the development and testing of devices, materials,
instruments, and control mechanisms that will provide
cardiovascular support, including total heart replacement.
75
Present and foreseeable techniques of general and
pharmacologic management of acute and chronic heart
failure or shock still leave a substantial fraction of
patients with compromised or fatally impaired heart
function. By supportive mechanical devices, it is possible
to assume some of the pumping function of the heart and
to relieve its work load. At present, such techniques
are applicable for brief periods in man and have been
employed for longer periods in experimental animals.
For example, recent studies of patients in the United
States have shown a definite reduction in the amount of
heart muscle damaged from heart attack when the heart
is assisted during recovery by means of a device called
the intraaortic balloon.
Partial and totally implantable heart assist devices
may be of significant use in the future for the correction
of acute and chronic heart failure. In recent studies
in the United States a device to assist the left side of
the heart has performed successfully in experimental
animals. Mechanical techniques for augmenting or sub-
stituting for the performance of the heart must be expanded
to encompass emergency temporary devices for short-term
management, extracorporeal assist pumps for intermediate
periods of use, long-term implanted heart assist devices,
and total artificial hearts.
Related opportunities and needs exist both to explore
the function of assisted circulation and to develop and
improve various components of circulatory support systems.
These components include compatible biomaterials , pumps,
actuators, energy transforming devices, implantable
energy systems, transcutaneous energy transmitters, and
control systems for the devices.
A U.S.S.R. delegation, headed by the U.S.S.R.
Minister of Health, Boris Petrovsky, visited the U.S. in
October 1974 to develop plans for implementing this
intergovernmental agreement. The major collaboration
efforts agreed upon in the October memorandum of under-
standing were familiarization and exchange of technical
aids and devices from each side; the holding of a joint
conference in 1975; and preparation for a future exchange
of samples of artificial heart devices, circulatory assist
devices, and their subcomponents.
Early in 1975, names of key U.S. and U.S.S.R. insti-
tutes planning to participate in this exchange were
telexed by each side. In April a Soviet delegation visitec
the U.S. to further develop collaborative efforts
initiated in October 1974, In addition, the U.S.S.R.
delegation had an opportunity to attend the annual meeting
of the American Society for Artificial Internal Organs, \
76
participate in the ASAIO international workshop on arti-
ficial internal organs, and visit several U.S. scientific
institutes specializing in the development of circulatory
assist devices and the total artificial heart.
A joint U.S.-U.S.S.R. meeting was held on April 28
and 29, 1975, to develop a new memorandum of understanding
under this agreement. The major items discussed were
scientists to participate in the program; exchange of
these scientists, equipment, and joint protocols; inclu-
sion in program of joint research and development of
circulatory assistance; exchange of lists of devices
and technical aids related to artificial heart and cir-
culatory devices; and joint publication of results of
studies and evaluation.
Fellowships, Contracts, Grants
During FY 1975, the National Heart and Lung Institute
funded six foreign fellowships, eight foreign contracts,
and ten foreign research grants. In addition, NHLI
supported seven research grants with foreign affiliations.
International Meetings and Visitors
All divisions of the National Heart and Lung Insti-
tute (NHLI) have sent personnel to numerous international
scientific meetings. NHLI staff members have actively
participated in these meetings by presenting papers, being
discussion panelists, or representing the NHLI at the
meetings. A brief description of some of the meetings
follows.
Division of Heart and Vascular Diseases
During FY 1975, a majority of the division's pro-
fessional staff participated in international meetings,
among which were the Meeting of the American Society for
Pharmacology and Experimental Therapeutics held in
Montreal, Canada; the Fifth International Symposium on
Drugs Affecting Lipid Metabolism, Milan, Italy; the
Canadian Cardiovascular Society Meeting in Vancouver,
Canada; the International Symposium on Lipids and Heart
Disease, Stockholm, Sweden; the First International Congress
on Twin Studies in Rome, Italy; Symposium on Hyper lipidemia
and Coronary Artery Disease, Tel Aviv, Israel; and the
WHO Meeting on the Effectiveness of Treatment in Mild Forms
of Hypertension, Madrid, Spain.
Division of Lung Diseases
The staff of the lung division was actively involved
in many international meetings in FY 1975. These included
77
the International Congress of Physiology and Satellite
Symposium held in New Delhi, India; the WHO Workshop on.
Epidemiology of Nonspecific Respiratory Diseases in Geneva,
Switzerland; the International Conference on Lung Disease
sponsored by both the American and Canadian Thoracic
Societies and held in Montreal, Canada; and the Inter-
national Conference on Membrane Lung Technology and Pro-
longed Extracorporeal Perfusion in Copenhagen, Denmark.
Division of Blood Diseases and Resources
Examples of international meetings attended by staff
members in this division during FY 1975 include the
Twenty-Fifth Congress of International Society of Hema-
tology, Jerusalem, Israel; Symposium on Fibrinolysis
held in Montreal, Canada; and the International Committee
on Thrombosis and Haemostasis in Basel, Switzerland.
Division of Extramural Affairs
The Director of the Division of Extramural Affairs
attended the Twelfth International Congress on Diseases
of the Chest held in London, England.
Division of Intramural Research
The staff of the Division of Intramural Research was
very active in international scientific meetings during
FY 1975. Many staff members attended more than one inter-
national meeting to discuss their own research findings
and to learn about research by scientists in other coun-
tries. Examples of some of the many meetings attended by
the DIR staff include the Second International Conference
on Cyclic AMP, Vancouver, Canada; symposium in honor of
Dr. Fritz Lipmann held in West Berlin, Germany; the second
International Workshop on the Human Gene Map in Amsterdam,
Netherlands; the Second Congress of Immunology, Brighton,
England; the Fifth Parathyroid Conference, Oxford, England;
the Laurentian Hormone Conference held in Mt. Tremblant,
Canada; the Pan American Symposium on Vasoactive Peptides
and Hypertension, Mendoza, Argentina; the Twenty-Fifth
Congress of the International Society of Hematology held
in Jerusalem, Israel; the Seventh World Congress of Car-
diology, Buenos Aires, Argentina; the Fourth International
Congress on Hormonal Steroids, Mexico City, Mexico; the
International Congress of Lipid Biochemistry held in Milan,
Italy; the Fifth International Symposium on Olfaction and
Taste, Melbourne, Australia; the South American Congress
on Pharmacology, Lima, Peru; the Fourth Workshop on Ex-
perimental Liver Injury on Pathogenesis and Mechanisms of
Liver Cell Necrosis, Freiburg, Germany; and the Inter-
national Congress of Nephrology held in Florence, Italy.
78
General
In addition, the institute has had representatives
at the following meetings dealing with international
research: Conference between the Royal Society of Medicine
of England and the Fogarty International Center (FIC) of
NIH to discuss proposals for future Anglo-American con-
ferences; Meeting of the Honorary Board of Trustees of
the Miguel Servet Fund of Spain; FIC's Conference on
International Health Costs and Expenditures at NIH; and
the International Conference on Women in Health.
During FY 1975 there were numerous international
visitors to the National Heart and Lung Institute. Some
of these visiting foreign scientists included the U.S.S.R.
Minister of Health, Boris Petrovsky; Dr. Katsumi Meguro,
Deputy Chief, Medical Affairs Division, Ministry of Health
and Welfare, Japan; Dr. Z. Pisa, Chief, Cardiovascular
Diseases, World Health Organization, Geneva, Switzerland;
and Dr. Lie, Chief of Cardiology at the General Hospital
in Jakarta, Indonesia. Also, NHLI staff discussed the
institute's programs with a number of visiting foreign
scientific writers.
Proposals For Future
International Programs
Proposals for future collaborative health research
with Brazil, Germany, India, and Poland were submitted
to the Fogarty International Center (FIC) in FY 1973 for
consideration. Action on three of these proposals is
still pending.
During FY 1974 the National Heart and Lung Institute
responded to inquiries from FIC concerning possible U.S.-
Argentina collaboration in the cardiovascular area.
In FY 1975, several discussions were held between the
staff of the National Heart and Lung Institute and rep-
resentatives of the Federal Republic of Germany (FRG) to
consider proposals for collaboration between U.S. and FRG
scientists. A summary of discussion between these two
countries was developed jointly and formally signed. A
workshop on artificial circulatory support, with particular
emphasis on the area of biomaterials development, testing,
evaluation, and the use of biomaterials in circulatory
devices will take place in FRG in FY 1976 and will be
attended by three American experts. At the conclusion
of this workshop, future plans for collaboration in the
field of artificial circulatory support will be discussed.
NATIONAL INSTITUTE
OF
ALLERGY AND INFECTIOUS DISEASES
The mission-related diseases of the National Institute
of Allergy and Infectious Diseases (NIAID) include many
that constitute insignificant health problems in the United
States but have a large impact on the socioeconomic and
health status of populations of many countries of the
world. The international benefits of the NIAID research
programs are of two categories: studies conducted in U.S.
laboratories on diseases of importance mainly to other
countries and studies conducted abroad that are either
funded by the institute or carried out in collaboration
with U.S. scientists.
In addition to the ubiquitous maladies, such as
hepatitis, tuberculosis, and the allergic, respiratory,
enteric, and sexually transmitted diseases, the NIAID
programs support research on most of the bacterial, fungal,
viral, and parasitic diseases that create large problems
in the tropical and subtropical countries of the world.
Those diseases include leprosy, cholera, dengue, oncho-
cerciasis, filariasis, trypanosomiasis, leishmaniasis,
schistosomiasis, malaria, and biologic control of the
vectors of disease. Probably the most significant con-
tributions stem from the extensive program for research
in immunology that supplies information on the disease
mechanism and new and improved methods for diagnosis,
treatment, and prevention.
Foreign research grants, while relatively few in
number, are of high caliber, having successfully competed
with a large number of other grant applications, many of
which are approved but unfundable at current budget levels.
These include grants to foreign institutions, grants to
U.S. institutions that fund part of the investigators'
studies abroad (e.g., ICMR program), and collaborative
research funded in certain countries with U.S. -owned local
currency. During FY 1975, 17 research grants were made
to investigators in 10 countries. The bulk of that funding
(72.3%) was for studies in immunology. Grants awarded to
U.S. investigators for training abroad were largely (65.7%)
in the field of immunology.
Tabular data on U.S. domestic research grants that
fund a portion of the studies are not readily available.
Funding of this type enables the research investigators
to conduct studies in areas where the diseases under study
are prevalent or endemic, but rare or nonexistent in the
United States. The nature of such studies can be illus-
79
80
trated by the following examples of studies conducted by
NIAID intramural scientists. They also illustrate some
of the studies on diseases of prime importance to other
countries .
Malaria
A videotape technique for study of the invasion of
red blood cells by malaria merozoites led to immuno-
chemical studies of the surface receptors involved. Based
on previous observations that Duffy negative blood group
West Africans had greater resistance to Plasmodium vivax
malaria, Duffy positive and negative red cells were used
in an in vitro system with P. knowlesi , to reveal that
Duffy positive red cells were invaded, whereas the Duffy
negative cells were resistant. In addition, removal of
Duffy blood group determinants by proteolytic enzymes, or
blocking the receptors with anti-Duffy serum, markedly
reduced invasion. These findings open the way to a search
for similar type receptors for other species of malaria
and possibly to exploitation of this knowledge for approaches
to rendering red cells resistant to merozoite invasion
as a method of treatment or prevention of malaria.
As a WHO short-term consultant, Dr. David J. Wyler
(LPD/NIAID) spent nearly 4 months in Gambia, West Africa,
studying aspects of the cell-mediated immunity in malaria.
Cases of falciparum malaria were found to have signifi-
cantly reduced circulating T cells during acute infection.
The finding of a ehemotactic factor for monocytes in
splenic extracts of mice and monkeys with malaria may
help to explain why splenomegaly is so prominent in
malaria. A review of old data on the influence of splen-
ectomy upon the course of established P. inui infections
in monkeys has revealed an interesting observation that
splenectomized animals cure themselves in contrast to
intact animals that have chronic infections for many years.
Filariasis
In collaboration with the health authorities of the
Cook Islands, South Pacific, who had scheduled antifilarial
drug treatment of the population of the out island of
Mauke, Drs . Eric Otteson, Louis Heck, and Peter Weller
(LCI, LPD/NIAID) spent 4 months on the island conducting
clinical and immunologic studies before, during, and after
the mass treatment. Through cooperation provided by Duke
University and TIB/NIAID, Marilyn MacQueen joined the
field team and conducted HL-A typing of a large portion
of the study population. The establishment of a field
laboratory on Mauke enabled the performance of function
tests and those possible only with fresh material. Many
specimens were collected and preserved for serologic
81
and biochemical analysis in the Bethesda laboratories.
This expedition provided an invaluable opportunity to
correlate the laboratory and clinical observations of
this disease and to observe the dramatic effect of die-
thylcarbamazine in clearing the circulating microfilaria;
90% reduction of worms in the first hour of treatment.
Additional studies were done on the dog, rodent, and
mosquito populations of the island.
Dengue and Other Virus Infections
The Pacific Research Section, LPD/NIAID, located in
Honolulu, Hawaii, is the center for a variety of collab-
orative studies and laboratory reference from many of
the islands and countries in the Pacific area. These
studies provide expert help to the health authorities of
those areas and some unique research opportunities for
Dr. Leon Rosen and his staff of research scientists at
the Pacific Research Section. The following are examples
of such studies.
Dengue type 1 virus reappeared after 30 years on the
Pacific islands of Nauru, Ponape, and Fiji, affording an
opportunity to study the behavior and manifestations of
this virus under relatively simple and known epidemiologic
conditions. Studies were done, also, on a flare-up of
dengue type 2 disease on Tonga and Tahiti. It was observed
that the fatal form of the disease (hemorrhagic and shock
syndrome) can result in individuals who have not previously
experienced dengue infections. In collaboration with the
SEATO laboratory in Thailand, it was demonstrated that
two to three times as many virus isolations were obtained
from dengue hemorrhagic fever patients by mosquito inoc-
ulation than by conventional cell culture techniques.
Studies of oral susceptibility to dengue virus among geo-
graphic strains of the vector mosquito Aedes albopictus
disclosed a similar pattern with all four dengue serotypes.
Studies on genetic differences in susceptibility of mos-
quito strains showed that significant changes resulted
from selective inbreeding, but no clear-cut mode of in-
heritance could be determined. A simple direct feeding
technique was developed to test the ability of mosquitoes
to transmit dengue viruses without feeding on a vertebrate
host.
Serum surveys of Southeast Asia and Pacific islands
have shown that human Chikungunya virus infections are
confined to the mainland, Indonesia, and The Phillipines.
However, antibodies to another group A arbovirus, Ross
River, were found in serum specimens from New Guinea and
the Bismarck and Solomon islands. Using a plaque reduc-
tion neutralization test, evidence of human infection
82
with four Phlebotomus (sandfly) fever group viruses was
found in specimens from Greece, Iran, Egypt, Sudan, and
Nigeria.
Dr. Robert B. Tesh spent 4 months studying the epi-
demiology of sandfly fever in Iran, as a collaborator
funded by the School of Public Health, University of
Teheran. The studies involved three geographic areas
and were used to train Iran workers in epidemiologic
techniques for sandf ly-borne diseases, which are impor-
tant public health problems in the Middle East. Many
human, animal, and insect specimens were collected and
transported to the Pacific Research Section for laboratory
investigations .
Clinical Research
During July and August 1974 Dr. Sheldon M. Wolff,
Clinical Director, NIAID, spent several weeks in Brazil
where he has gone each summer for the past 3 years. During
these visits he lectures to students and faculties, sees
patients, makes rounds, and meets with individual scien-
tists to review work and offer advice and ideas. Out
of these visits has grown a very close relationship
between several of the senior faculty at the Federal
University of Rio de Janeiro and the Clinical Director.
For example, two senior scientists from the Institute of
Biophysics in Rio have spent time working, and one is now
in training in LCI, NIAID. The Clinical Director, NIAID,
has already accepted invitations to return to Brazil next
summer to lecture in Sao Paulo and Rio de Janeiro.
The Clinical Director, NIAID, also spent time in
July 1974 and again in June 1975 with collaborators at
the Pasteur Institute in Paris, France. These investi-
gators have prepared materials that appear to have pro-
perties of inducing nonspecific resistance to infection,
and this work has resulted in a paper recently submitted
for publication. Plans are under way to eventually evaluate
these components here at NIH in human beings.
In June 1975 the Clinical Director, NIAID, presented
an invited lecture at one of the major symposia at the
International Congress of Nephrology in Florence, Italy.
Approximately 1,500-2,000 people from all over the world
attended this symposium.
In August 1974 the Head, Biologic Structure Section,
LCI, NIAID, visited a number of laboratories in South
Africa where he presented lectures and discussed research
with senior scientists from the University of the Witwater-
srand and South African Society of Patholoqy (where he
taught a course in immunology), Johannesburg, South Africa.
83
Dr, Charles Kirkpatrick f Head, Clinical Allergy and
Hypersensitivity Section, LCI, NIAID, visited in March
1975 the Rheumatic Fever Project in Cairo, Egypt, as a
consultant. This is a collaborative project of the
Center for Disease Control, DHEW, and the Ministry of
Health of Egypt.
Scientific Communications
The NIAID is conducting two experiments for the
development of new and improved methods for informal
communications between research investigators. These
involved a rapid and frequent distribution of short,
informal, written communications, and the use of a commun-
ication satellite. Both experiments include scientists
from many countries and thus are international in opera-
tion.
The scientific memoranda contain short, informal
progress reports on current research, scientific comments,
and any other informal communication pertinent to the
research subject covered. Communications are photoreduced
and reproduced, without editorial attention, and distributed
to the participating scientists monthly or quarterly.
Scientists from 47 countries, plus the United States,
participate in this project. Separate scientific memo-
randa exist for interferon, hepatitis, leprosy, hyper-
sensitivity disease, sexually transmitted disease,
transfer factor, and nucleic acid recombinants.
The satellite experiment uses the NASA ATS-1 satel-
lite maintained in geosynchronous orbit approximately
23,000 miles above the equator in the middle of the
Pacific Ocean. The satellite coverage area includes the
whole Pacific Ocean and as far east as Bethesda, Md.
Anyone in the coverage area, equipped with relatively
small and inexpensive FM radio transceivers with proper
frequencies, can communicate directly via the satellite.
The NIAID project is purposed in determining the useful-
ness of this method of informal communication to bio-
medical research investigators. The project has involved
scientists on field trips or in their laboratories in
many of the countries and island areas of the Pacific.
Geographic Medicine Branch Program
This Branch of NIAID manages three international
programs: the U,S«- Japan Cooperative Medical Science,
the International Centers for Medical Research, and the
Cholera Research Laboratory in Dacca, Bangladesh.
84
U.S. -Japan Cooperative
Medical Science Program
The U.S. -Japan Cooperative Medical Science program
was initiated in January 1965 as the result of a meeting
between the Prime Minister of Japan and the President of
the United States. The two heads of state agreed to
undertake a greatly expanded, joint cooperative research
effort in biomedical sciences to improve the health of
the people of Asia. The disease categories considered
to be of particular importance included cholera, leprosy,
malnutrition, the parasitic diseases schistosomiasis and
filariasis, tuberculosis, and the viral diseases rabies,
dengue hemorrhagic fever, and other selected arboviruses.
In 1972 environmental diseases was added as a program
interest.
The U.S. -Japan Cooperative Medical Science program
operates within a bilateral government framework. Never-
theless, it may involve scientists and facilities in third
countries and/or collaboration with international or other
organizations. The relevant regions in Asia, although not
specifically defined, are generally understood to include
the Republic of Korea on the north, India and Pakistan
to the west, and other adjacent nations in the broad
Pacific basin.
The United States and Japan each support the cost of
their own scientific projects and meetings.
1. Cholera
The cholera program has completed a toxoid field trial
in some 92,000 persons in the cholera endemic area of
Bangladesh. The fall cholera epidemic was unusually severe
this past year and provided a most rigorous test of the
protective effect of antitoxic immunity to El Tor cholera
infection. The conclusion from the field trial of two
injections of cholera toxoid (100 mg each) is that pro-
tection from antitoxic immunity was transient with no
improvement over licensed cholera vaccine. However, this
toxoid produced a higher level of protection in the child-
ren under 14 years of age than in adults. This finding
was unlike earlier field trials with cell vaccines that
always gave better protection in the adults and lower
protection in children. The level of somatic antigen in
the toxoid did not stimulate vibriocidal antibody pro-
duction in the native population. This confirms the high
degree of purity of this toxoid. Work now centers on how
to enhance the limited protection seen in the first field
trial of a cholera toxoid.
85
Important observations have been made on the effect
of local immunization on resistance. Most significant is
that if the dog model was primed with one parenteral in-
jection of toxoid, followed in 1 month by a series of
oral doses, there was prolonged protection against cholera
challenge. Serum antitoxin levels, however, were notably
low. These findings have been confirmed in rats. A
similar dose schedule in rats called forth the maximum
number of specific antitoxic plasma cells in the lamina
propria of the small bowel. Local response required
local stimulus, and it was shown that lymphocytes derived
from gut-associated lymphoid tissue, such as Peyer ' s patches,
passed through the thoracic duct circulation and returned
to the small bowel in the absence of local antigen. This
information on local immunity underlines the importance
of further studies on the local immune mechanisms.
A chemically induced nontoxinogenic mutant of a highlibrio
toxinogenic strain of V cholerae has been fed to volunteers
and found to multiply in the gut without producing disease.
These volunteers were resistant to challenge with live
virulent organisms. The mechanism of resistant is assumed
to be antibacterial and the method may hold some promise
for a future, live oral vaccine.
Detailed studies on the structure of the cholera enter-
otoxin molecule has indicated that there were two subunits,
designated A and B. Subunit A, the adenylate cyclase-
activating component of the enterotoxin molecule, is com-
posed of two chains designated Al and A2 linked by disulfide
bonds. Amino acid sequencing studies have been started
in several laboratories.
The U.S. and Japanese cholera panels have catalyzed
a cooperative venture between the two countries to stan-
dardize the characterization of noncholera vibrios. Two
laboratories in each country are involved. The plan is to
share type cultures from each country's collection and
compare biochemical and serological results with the idea
of arriving at a mutually agreeable classification system.
The United States has sent 86 type cultures to Japan, and
the Japanese have sent 38 type cultures from their collec-
tion. The four laboratories are busily engaged in applying
their testing schemes to these new cultures. Early results
indicate that 31 of the Japanese cultures may be similar
to U.S. type cultures.
Studies on the incidence of diarrhea caused by enter-
otoxin producing E coli are progressing well. The first
40 cases of diarrhea studied in a pediatric hospital in
Brazil indicates as many as 50% of the children had lactose
fermenting organisms that produced the cholera-like, heat-
86
labile toxin as the only fecal pathogens. So far, very
few E. coli have been found that produce only heat-stable
toxin. Thus, the importance of strains that produce only
heat-stable toxin in human disease remains unknown. The
role of enterotoxigenic E. coli should come into better
focus as more cases are added to the study. Material
from these E. coli studies is also being examined for the
rheovirus-like agent associated with some infantile
diarrheas .
Considerable progress has been made on isolating and
characterizing a low-molecular-weight, heat-labile toxin
from E. coli . The material has been extracted from the
culture and reduced to near electrophoretic homogeneity
by chromatographic techniques. It is active biologically
at the nanogram level and shows strong cross reactions
with antisera produced by purified cholera toxin. Attempts
are under way to achieve higher yields of this material.
2. Environmental Mutagenesis/Carcinogenesis
Stimulation of the development of better methodology
to screen chemicals before they are released into the
environment, as well as to provide a thorough evaluation
of chemicals already present in the environment, is one of
the primary activity areas of this panel. Exploratory
experiments on various classes of chemicals (drugs, food
additives, pesticides, cosmetics, industrial compounds,
etc.) have already shown that there are numerous examples
of agents that have genetic activity in experimental
organisms. The main question is to determine their effect
on man. In addition, recent studies have shown that there
is some correlation between carcinogenic and mutagenic
activity and evidence of mutagenic activity in experimental
organisms may mean that a chemical not only presents a
genetic hazard to man but a carcinogenic hazard as well.
To ensure the effectiveness of any screening program
established, new approaches will have to be developed for
population monitoring and epidemiology. Better tests are
needed to evaluate the effects of accidental or deliberate
exposure to mutagenic agents on somatic cells and germ
cells in man. Exposure of somatic cells may induce damage
that will make an individual more susceptible to the
development of various types of cancer; exposure of germ
cells may induce damage that will be transmitted to future
generations .
One of the major deficiencies in testing is the lack
of assays that can be made on somatic and germ cells of
man for the production of gene mutations. In one project
an attempt is being made to develop an assay for gene
mutations induced in germ cells. By using loci that pro-
duce proteins that can be studied with starch gel electro-
87
phoresis, it is possible to look for "electromorphs"
(altered proteins with different electrophoretic mobility)
or "amorphs" (changes that result in complete loss) at
specific loci. The program of research seeks to identify
additional loci at which such analyses can be made so that
numerous tests can be performed on progeny of the same
treated animal.
In another project the research is directed toward
the development of an assay in mice that will permit
assay of a random sample of loci over the entire genome.
Development of mouse strains containing large numbers of
inversions will permit assay of the recessive lethal
mutations occurring in these regions.
The development of better methods for detection of
point mutations in somatic cells is the objective of
another project that utilizes blood samples to determine
the frequency of variant red blood cells. Normally, only
a very low percentage of erythrocytes contain fetal
hemoglobin. An assay is being developed with selective
antisera to determine the frequencies of such variants
quantitatively .
The development of assays for gene mutations at spe-
cific loci is under way in another project utilizing human
fibroblasts in culture. This system utilizes the hypox-
anthine-guanine phosphoribosyltransferase (HGPRT) locus
as well as the azaguanine phosphoribosyltransferase (AGPRT)
locus. Present data clearly indicate that drug-resistant
mutants result from genetic changes at these two loci
that result in structurally modified enzymes. The spon-
taneous frequency of variants at each locus has been
determined in various individuals as has the induced
frequencies obtained after mutagenic treatment.
The better detection of the genetic activity of air-
born environmental pollutants is the objective of an
additional project with the wildflower Tradescantia . By
using a strain heterozygous for flower petal color, it
is possible to observe pink and colorless sectors in
normally blue flower petals and stamen hairs. The assay
system is a very sensitive detector of the mutagenic
activity of radiation, and exploratory experiments are in
progress to determine its sensitivity to various chemicals
including known chemical mutagens.
The collaborative efforts of the United States in
this program are provided through the National Institute
of Environmental Health Sciences and the National Institute
of Allergy and Infectious Diseases.
88
3. Leprosy
The three areas of leprosy research that continue
to receive special emphasis include immunology, chemo-
therapy, and cultivation and transmission in animal models,
Excellent progress has been made in preparing trans-
fer factor (T.F.) to be used in a controlled clinic trial
to evaluate the immunotherapeutic response of this agent
in the treatment of lepromatous leprosy. Efficacy of
T.F. will be determined by in vitro laboratory studies
that measure cellular mediated immunity, as well as by
clinical assessment to evaluate any improvement of local-
ized lesions. It is anticipated that at least 2 years of
continuous observation will be required to draw conclusive
results on the efficacy of this form of immunotherapy.
The fourth annual surveillance of post- treatment of
leprosy patients among the Pingelapese population was com-
pleted in February 1975. At present, the investigators
have concluded that eradication of leprosy in an endemic
population by use of DADDS for preventive treatment can-
not be totally effective without simultaneous and con-
tinous drug control of all bacilliferous cases. Studies
will continue in FY 19 76 to determine if mass treatment
with DADDS is associated with the emergence of sulfone-
resistant infections.
Studies on the in_ vitro cultivation of Mycobacterium
lepraemurium were initiated by a research contract during
the past year. Preliminary work has demonstrated that
fetal calf serum is superior to goat or bovine sera as a
supplement to Nakamura's basal medium. A thorough evalua-
tion of the efficiency of different sera is in process.
Other factors, such as microaerophilia and levels of
aerobiasis, are under investigation to determine methods
and techniques to enhance in vitro cultivation of M.
lepraemurium . The nine-banded armadillo continues to be
an outstanding animal model for the in vivo cultivation
of large quantities of M. leprae . Steps have been taken
to establish and support a continuous colony of armad-
illos infected- with M. leprae . This potential source of
M. leprae will provide a strong stimulus to future studies
to ascertain the immunochemistry and antigenic properties
of the various purified components of the organism.
4. Parasitic Diseases
A major breakthrough in the development of S mansoni
culture systems for studying the growth and development
of schistosome parasites was achieved when one of our con-
tractors established a cell line from embryos of the
snail host, Biomphalaria glabrata. Suitable media and
89
culturing techniques have been described in detail and
are being utilized by investigators in studying larval
stages of S. mansoni in vitro .
Studies of the possibility of the biological control
of schistosomiasis have shown that Biomphalaria glabrata
snails have the potential to develop acquired resistance
to trematode infections. This finding will make possible
the study of the basic principles of snail immunity.
A major granuloma-inducing antigen has been isolated
to a single band on polyacrylamide gel electrophoresis.
A radioimmune assay has been developed using this antigen,
and the development of antibody against it correlates
with the waning of granulomatous hypersensitivity.
A joint meeting with the Japanese panel was held in
August 1974 in Nagasaki, Japan, and a workshop on "Animal
Models of Filariasis" was held in Bethesda, Maryland, in
April 1975. At this workshop it was reported that four
species of monkeys had been inoculated with a Tongan sub-
periodic strain of Wuchereria bancrof ti resulting in
developing worms. This was the first definitive evidence
that W. bancrof ti , thought to be an exclusively human
parasite, will mature in monkey hosts. This finding should
expand the scope of filariasis research to include a wide
variety of studies on this important human disease.
Ultrastructural studies of the development of Brugia
Malayi larvae in the mosquito vector's flight muscles have
demonstrated a specialized surface that is suggestive of
absorptive function during a phase of rapid growth and
development. This is the first demonstration of such a
function in filarial larvae, and it is hoped that supple-
mentary biochemical studies will follow.
5. Tuberculosis
The research sponsored this past year by the tuber-
culosis program again focused on the immunologic aspects
of tuberculosis. The monkey model for studying aerosol
BDG vaccination with aerosol challenge continues to be
investigated. Previously, it was shown that the route
of administration of BCG vaccine significantly affects the
degree of protection against aerosol challenge with
virulent tubercle bacilli. Inhalation of the vaccine or
administration by the intravenous route confers a higher
degree of resistance to challenge than does intracutaneous
administration of vaccine. The protection afforded by
aerosolized vaccine was also found to be related to the
total dose of viable units administered. The highest dose
tested, 105 (vu) was the most effective. As an adjunct to
this study, it was found that previously sensitized guinea
90
pigs did not display clinical signs of pulmonary distress
after exposure to aerosolized BCG; however, there was an
indication of slight, but statistically significant, in-
crease in total airway resistance following exposure.
A study is now under way to determine the duration
of protection afforded by aerosolized BCG as opposed to
intracutaneously administered BCG. Deaths in animals
challenged 8 and 28 weeks following vaccination are less
than in the control group. Less pulmonary infiltrate is
seen in radiographs of those animals receiving the intra-
cutaneous vaccine. As a follow-up to the guinea pig pilot
study with BCG-sensitized lungs, a more comprehensive
study with monkeys has recently been initiated.
The relationship of delayed-type hypersensitivity to
one or more microbial antigens in the immunized host and
the expression of cell-mediated immunity (CMI) against a
virulent challenge organism have been clarified. It has
been established that a sensitizing preparation must be
used if an effective antibacterial resistance is to be
developed. Large doses of living bacilli may induce an
effective CMI in the apparent absence of peripheral DTH
but transfer studies showed that the anergic animals still
contained sensitized lymphocytes capable of transferring
tuberculin sensitivity to normal recipients.
Migration inhibitory factor (MIF) and a new type of
interferon (type II) are released into the circulation
after mice have been sensitized intravenously with viable
BCG and challenged later with old tuberculin. In this
in vivo production of mediators the activity of MIF was
at least 100-fold greater than the MIF induced in_ vitro .
Two components of BCG, the protein PPD and the lipid P3
necessary for the production of MIF, were also necessary
for the induction of resistance to a virulent aerosol
challenge. In preliminary studies, the production of MIF
in vivo in mice seems to be associated with both B and T
lymphocytes. Other studies involving the basic immune
mechanisms of the mycobacterioses continue.
This year a task group convened at the National In-
stitutes of Health to discuss the role of soluble mediators
of cellular immunity in tuberculosis. These substances
have been shown to be of immense biological and clinical
importance and are the subject of widespread investigation.
A general overview of the problem area was discussed, those
areas where the U.S. -Japan program could provide support
were identified, and a list of priorities to facilitate
orderly progress of the research were developed.
Highly characterized and standardized mycobacterial
materials continued to be available to qualified scientists
working in tuberculosis and related areas.
91
6. Viral Diseases
Studies have established that protection from virulent
intracerebral challenge with rabies virus is directly
dependent on the level of specific neutralizing or lytic
antibody present at the time of challenge. Inactivation
of rabies virus by beta-propiolactone was evaluated by
the rabies fluorescent focus inhibition test (RFFIT) and
was shown to leave no detectable residual infective virus.
The RFFIT was found to be more reproducible than the mouse
neutralization test, requires less time for completion,
and is less expensive. A major rabies glycoprotein has
been extracted by exposure to alkaline EDTA. Physical
chemical procedures attest to the purity of the glyco-
protein preparation. This protein consists of a single
polypeptide chain with a molecular weight of 70,000 daltons.
Its biological activity was demonstrated by immunization
of hamsters, rabbits, and mice.
Recent studies on skin biopsy material from dengue
patients indicate that skin rashes in these cases are
likely to be immunopathologic in nature. It also has
been shown that in acute stages of dengue hemorrhagic
fever and dengue shock syndrome, B lymphocytes and certain
dengue antigen antibody combinations form immune complexes
on cell surfaces. In studies of the epidemiology of
dengue virus in the jungles of Malaysia, it has been shown
that dengue is a zoonosis involving wild monkeys in the
primary rain forest. Recent emphasis has been on attempts
to identify the mosquito species that serves as the
important jungle vector. Evidence has been obtained showing
that enzootic dengue, involving at least three of the
four known virus types, occurs in the high canopy of
isolated primary rain forest and that Aedes niveus mosquitoes
are most likely the jungle vectors. Other vector studies
have uncovered a marked variation in susceptibility of
dengue viruses and the stability of this character from
generation to generation. This could be of great impor-
tance in controlling epidemic dengue. Results suggest that
it might be possible to achieve disease control in an area
by replacing a susceptible vector population with a more
refractory strain of the same species.
7 . Malnutrition
Although malnutrition is one of the categories included
under the U.S. -Japan program, this area is partially ad-
ministered by NIAMDD and will be included as part of its
report.
92
International Centers
for
Medical Research (ICMR) Program
In response to the expressed desire of the Congress
(PL 86-610) , a program for the International Centers for
Medical Research was established in 1960 by the National
Institutes of Health "to advance the status of the health
sciences in the United States and thereby the health of
the American people" by expanding collaborative research
between U.S. universities and selected foreign institutions
and investigators. Since 1968, this program has been
administered by the National Institutes of Allergy and
Infectious Diseases.
The four grants funded under this program are awarded
for 5 years with continued support contingent upon pro-
gram review at the end of each year of operation. One
of the most important features of this program is that
of long-term support, as contrasted with the transiency
that has characterized a number of other international
projects. This is a necessary ingredient for the full
development of university careers in science in order to
effectively utilize the international medical experience
of individual scientists. This program provides oppor-
tunities for established and highly competent investigators
to realize valuable research opportunities abroad without
losing their university affiliations and faculty appoint-
ments. The long-term support of the ICMR does not represent
a form of foreign aid since the primary objective is a
collaborative effort in biomedical research of specific
relevance to the health of the American people and to
the U.S. scientific community. The four current ICMR
grants were renewed for an additional 5 years beginning
FY 1975.
1 . Purpose and Scope
The ICMR program has as its principal objective the
provision of high quality research and scientific oppor-
tunities for Americans in the broad fields of geographic
medicine and in response to the special opportunities
existing with each ICMR framework. The length of the
research period overseas is a discretionary concern of the
ICMR program director and is obviously determined by both
the interests of the prospective investigator and the
specific opportunities available within the given ICMR
unit. Consistently, the emphasis is upon the quality
rather than the quantity or duration of the research pro-
grams .
93
The aggregate ICMR units are serving increasingly as
a national resource for utilization by senior, as well as
less experienced, scientists to create a comparatively
modest pool of investigators with a sustained career
interest in international or geographic biomedical research.
In this regard, the ICMR program directors are encouraged
to establish a selective, interdisciplinary scientific
program. Their activities encourage and accommodate a
number of parent university departments other than the
department that primarily sponsors the ICMR operation.
Particular advantage is taken of special strengths within
the overall parent university, including opportunities
in health-related fields outside the classical confines
of tropical medicine. As far as is possible, the ICMR
core grant is used for research support at the offshore
ICMR site rather than at the parent domestic university.
In this regard, it is accepted that some preparation
preliminary to an overseas assignment is necessary and as
many items of equipment and supplies as feasible are
purchased in the United States.
Discussion of the four institutions participating in
the ICMR program at present and their respective areas
of research interests follows:
1. Johns Hopkins University (Baltimore, Md.)
Program Director: Dr. Frederik B. Bang
Several years ago, Johns Hopkins University transferred
its operations from Calcutta to Dacca, Bangladesh, to
take advantage of the facilities at the Cholera Research
Laboratory and to initiate a series of studies on Bang-
ladesh disease problems that had been previously studied
by the Hopkins group in India. Program emphasis continues
to be directed toward the epidemiology and management of
human diseases of large populations and the ecology and
behavior of animals living in close association with man.
Research on cholera and other diarrheal diseases consti-
tutes the core of the program and includes studies of the
effect of zirconium oxychloride on fluid loss, oral sucrose
therapy, collection of toxinogenic strains of Eschlerichia coli ,
studies of leukemoid reactions and hemolytic anemia in
shigellosis, determination of T and B cell response in
Shigella infection, and a study of the association between
malnutrition and diarrheal diseases. Related studies are
directed at the effect of protein calorie malnutrition in
immunological competence. Three programs were conducted
during the past year on parasitic diseases: epidemiology
of endemic filariasis; epidemiology of echinococcosis;
and a study of local malaria vectors.
94
Ecological studies have been initiated to determine
the contribution of rodents and insects to crop and store
grain loss, to correlate the rate of fish growth with food
sources and water quality, and to determine how to maximize
the benefits of dung beetles, distribution of feces in
soil, and maintenance of soil porosity.
2. University of Maryland (Baltimore, Md.)
Program Director: Dr. David Clyde
The University of Maryland, with the participation
of its School of Medicine and collaborating with the
Institute of Hygiene, Lahore, has undertaken a varied
research program in West Pakistan. This program during
the past year has continued to be based on studies of the
genetics of important insect vectors of virus and para-
sitic diseases. The objective is production of strains
with lessened vector ability. Associated with the inves-
tigation of the genetics of Anopheles stephensi , a prin-
cipal carrier of malaria in central and western Asia, has
been an examination of the resistance of local strains of
this mosquito to insecticides, an increasingly serious
problem for the malaria eradication campaigns of Pakistan
and neighboring countries. Genetic manipulation of Culex
tritaeniorhynchus , important in the transmission of Japanese
B encephalitis, West Nile, and Chikungunya viruses and
ranging from East Asia to West Africa, is yielding results
that will permit early field application on a limited scale.
3. University of California (San Francisco, Calif.)
Program Director: Dr. Albert Rudnick
The University of California, with the participation
of the Hooper Foundation, the School of Public Health, and
the Medical School, is collaborating with the Institute
for Medical Research, Kuala Lumpur, Malaysia and the
University of Malaya. This international center continues
to place strong emphasis on infectious diseases transmitted
from animals to man. Because of the long-standing research
interest and experience in studying the fundamental prob-
lems of human ecology at the University of California, a
collaborative program has been developed embracing medical
zoology, microbiology, and parasitology. The scope of this
collaborative endeavor has now been expanded to include
related sociocultural research and medical genetics.
Long-term research projects in Malaysia and California
are based on three general laboratory programs : the Ar-
bovirus Research Unit; the Parasitology Laboratory; and
the Medical Anthropology and Rural Health Research project.
The arbovirus research is focused on the epidemiology
and ecology of dengue virus and the relationship of this
95
virus to mosquito-borne hemorrhagic fever. A jungle
reservoir (monkey) has recently been demonstrated for
dengue. The parasitologic research is based on studies
of trematode ecology and interactions of various para-
sites in the snail host and the ecology of Malayan pen-
tastomes or tongue worms. The snail trematode antagonism
studies are directed toward the biologic control of schis-
tosomiasis, and this ICMR represents a leading world
resource for this important field research.
Abundance, distribution, life cycle, and ectopara-
sites of rodents closely associated with man have also
been studied. Work on the possible role of the Indian
fruit bat as a reservoir of human viral infections has
been completed. Other field studies include the inves-
tigation of bacteria and viruses pathogenic for man in
monkey populations. Sociocultural studies concerned with
Malayan attitudes toward health and nutrition and the in-
fluence of native and western practitioners of medicine
on these attitudes have been undertaken by a number of
variously trained, medically oriented social scientists.
4. Tulane University (New Orleans, Louisiana)
Program Director: Dr. Paul C. Beaver
Tulane University, with the participation of the
Department of Tropical Medicine and Public Health, other
departments of the Medical School, and the Department of
Anthropology and Sociology, has been collaborating with
the* Universidad del Valle, Cali , Colombia. The research
work falls into three general areas : Nutrition and meta-
bolic diseases; Infectious diseases; and Behavioral science.
Parasitological research includes classic life cycle
approaches to the epidemiology of paragonimiasis, trypan-
osomiasis, and animal malaria, taxonomic studies of
Culicoides and tabanids, an overall study of the parasites
of bats, and a broad program of filariasis research with
emphasis on onchocerciasis. Two principal virological
studies have just been initiated in cytomegalovirus and
on patients with Guillain-Barre disease. The objectives
of the mycology program are centered primarily on the
systemic mycoses, especially paracoccidioidomycosis, the
most important deep mycotic infection in Colombia. These
studies encompass both epidemiology and immunology.
The nutrition program at the ICMR in Cali encompasses
a variety of research activities including studies of the
malabsorption syndrome in protein calorie malnutrition,
enterobacteriology of protein calorie malnutrition, thyroid
function studies in adult malnutrition, evaluation of
protein quality for children, and a study of the nutrition
and feeding habits of a community. A related study has been
concerned with immune responsiveness in normal and mal-
96
nourished infants.
Currently, the behavioral science program is empha-
sizing shorter-term, small projects in five areas: social
psychiatry and behavioral disorders; evaluative research
and health systems; medical anthropology; social demo-
graphy; and health service utilization.
Cholera Research Laboratory,
Dacca, Bangladesh
The Cholera Research Laboratory (CRL) , Dacca, Bang-
ladesh, continued operations during fiscal year 1975,
financed principally by the Agency for International De-
velopment (AID) . Through a participating agency agreement,
the National Institute of Allergy and Infectious Diseases
(NIAID) provided both the administrative and scientific
support to the CRL. In addition to this staff support by
NIAID, the Center for Disease Control deputes two EIS
officers to Dacca; the Government of Bangladesh provides
space in the Institute of Public Health and the Rural
Health Center in Matlab Thana, plus utilities and a cash
contribution. The governments of Australia and the United
Kingdom have also contributed funds, equipment, and
services to the CRL.
The research program at CRL centers around diarrheal
research involving field studies and clinical research.
The past year demonstrated the capabilities of the CRL to
handle a large field trial involving over 90,000 persons
in a test of a cholera toxoid. The number of cases of
cholera during the fall epidemic provided an excellent
test of antitoxic immunity against cholera. The protection
was of a low level and transient with no improvement over
licensed cholera vaccine. Of particular interest was the
higher level of protection in the children under 14 years
of age. This was directly opposite to early cholera
vaccine trials that demonstrated the lowest protection in
children and highest in adults. Methods of improving this
protection are being sought. The field trial population
will remain under surveillance to measure the effect of
the toxoid on the second cholera season.
The development of the oral electrolyte solution for
treatment of dehydration has received worldwide acceptance.
However, the difficulty of finding glucose for the formula
is a problem in some areas of the world. Further testing
at CRL has found that contrary to earlier data, sucrose
appears to be as effective in aiding electrolyte absorption
as glucose. A new formula including sucrose is being
tested in diarrhea patients.
97
The studies measuring the effect of a low pH and
fluid secretion in the small bowel have revealed the rapid
loss of the villous tips lining the small bowel. It is
assumed that the sudden reduction in fluid loss is due
to removal of these toxin-activated cells that are hyper-
secreting. Animal studies are continuing, and a clinical
protocol has been submitted for approval. The value and
practicality of this treatment have not been firmly
established yet.
In a study of 50 patients with diarrhea of unknown
etiology, nearly one third were found to have toxigenic
Escherichia coli present in the bowel. In addition to the heat-
labile toxin found in other toxigenic E. coli studies,
there were two strains of E. coli producing only the heat-
stable toxin. This is the first recognition in Bangladesh
of an E. coli strain that produces only the heat-stable
toxin. Its relation to disease production in man is not
yet known.
Shigellosis continues as a major problem in Bangladesh.
In addition to the leukomoid reaction in severe cases,
one third to one half these cases also develop acute
hemolytic anemia associated with erythrocyte fragmentation.
Blood transfusions will correct the anemia, but the patho-
genesis remains unknown. It was also noted that shigella
infection causes a depression of the percentage of T
cell rosette-forming lymphocytes, while B cells remain at
normal levels. In addition, there is a large population
of cells not countable as T or B cells. These "nil" cells
amounted to 10 to 60 percent of the total lymphocytes,
compared with 3 percent in normal individuals. It is not
certain whether these "nil" cells are another type of
lymphocyte, immature lymphocytes, or a new undescribed
cell.
Over half of all patients coming to CRL hospitals are
seriously malnourished. The CRL is taking advantage of
this fact by studying the effect of malnutrition on diar-
rheas. The malnourished patients, on the average, purged
longer than comparable patients in better nutritional
status. There was no noticeable effect on volume/unit
of time. This extended period of diarrhea may be due to
the prolonged life of the mucosal cells activated by
cholera toxin in patients with malnutrition. Another study
was designed to relate malnutrition and infection through
cell-mediated immunity. The children below the 50th per-
centile of Matlab standards for weight and height have
twice the incidence of allergy as children above the 50th
percentile. This suggests that cell-mediated immunity
status may be an important independent determinant of
diarrhea in addition to nutritional status.
98
The demographic data available from the 250,000
persons in the surveillance area are being recognized as
a unique data base unavailable in any other developing
country. With the continuing census information, it is
possible to do rate studies in this population that
cannot be done in other developing countries due to the
lack of a definitive denominator. A 3 year study on the
effect of birth control measures is under way.
NATIONAL INSTITUTE OF ARTHRITIS f
METABOLISM, AND DIGESTIVE DISEASES
U.S.-U.S.S.R. Cooperative
Science Agreement
A memorandum of scientific cooperation between
Soviet and U.S. rheumatologists was signed May 22, 1975,
at the National Institutes of Health. Dr. Ronald W.
Lamont-Havers , then Acting Director, NIH, and a specialist
in the rheumatic diseases, and Professor V. A. Nassonova,
Director, Institute of Rheumatism, Moscow, signed an
agreement to formalize the continued exchange of scienti-
fic data and personnel in the field of arthritic diseases
between these two countries.
This agreement, the third in a series of cooperative
memoranda signed last year in Moscow, culminated 5 days
Of intense discussion on two major areas: evaluation of
different methods of drug treatment for rheumatoid
arthritis (RA) and systemic lupus erythematosus (SLE) ,
the latter an autoimmune disorder of the connective tissue
that affects the structure and function of skin, joints,
and internal organs; and microbial and immunologic
studies of RA and SLE.
Through a series of bilateral exchanges of scientific
personnel, the program will emphasize studies of anti-
viral, humoral, and cellular immunity in SLE and RA and
the exchange of information in immunologic and other
research methods. In addition to these and other planned
activities, reprints and lectures pertinent to problem
areas will continue to be exchanged. A symposium to
evaluate preliminary results and plan future projects is
scheduled for Moscow, late summer 1976.
The cooperative study of the arthritic diseases is
the fourth major collaborative undertaking in the health
sciences between the United States and the U.S.S.R.
Earlier agreements, including those in vascular diseases,
cancer, and environmental health, were begun under the
initial 1972 agreement on cooperation in the field of
medical science and public health.
The accord was formulated by the Soviet delegation,
including Professor Nassonova and colleagues Drs. A.
I. Speransky and M. M. Ivanova, and U.S. scientists headed
by Drs. Lamont-Havers, William Batchelor, and Alfred
Steinberg, NIAMDD.
99
100
Nutrition Studies in South America
In the area of malnutrition and its possible effect
on mental development, Dr. Adolpho Chavez and associates
(Mexico City) have documented the nutritional, sociologic,
psychologic, and environmental factors surrounding their
subjects to determine their influence on physical and
mental development. At the end of 3 years, the investi-
gators have been able to demonstrate that mothers given
food supplements produce more milk and thus maintain
a nutritionally adequate plateau for at least 24 weeks
after delivery. Significantly, the physical activity of
children who received food supplements was higher and
became increasingly elevated after the first year, reaching
a level six times higher than that of the unsupplemented
group by 2 years of age. Furthermore, the unsupplemented
group showed a 20-week retardation in neurologic development
in the lower extremities and had lower scores in language
ability. Both groups suffered a similar number of
infections, but the total number of days of illness and
the severity of the infections were significantly higher
in the unsupplemented group.
In other studies of malnutrition and infection, Dr.
Leonardo Mata of the Institute of Nutrition of Central
America and Panama has documented the high incidence of
bacterial and viral infections and infectious diseases
of all types, including malnutrition, in children living
under conditions characteristic of developing countries.
Dr. Mata's graphic demonstration of the association between
frequency of infections in preschoolers and their impaired
physical growth and development led him to conclude that
weight at birth is the best predictor of child survival.
Only 2 of 81 infants weighing at least 2,750 grams at
birth died within the first 6 months; no deaths were
recorded among babies weighing 3,000 or more grams.
Survival rates decreased sharply with lower birth weights.
Because these deaths largely resulted from diarrheal
or respiratory disease, they were attributed in the main
to decreased resistance to infection. There was evidence
that the effect on the fetus of the mother's malnutrition
during pregnancy was mediated through a higher frequency
of intrauterine infections, as judged by levels of
immunoglobulins in blood samples taken from the infants
at birth.
These observations have awakened widespread interest
in the relationship between maternal nutrition and infant
birth weight with subsequent morbidity, mortality, and
physical growth, as influenced by the interactions of
malnutrition with infection in mother and child.
101
U^S,^- Japan Cooperative
Medical Science Program
Specific research projects, carried out abroad
among populations with nutritional deficiency diseases,
are designed to find solutions to complex malnutrition
problems. These projects are largely funded through
the U.S. -Japan Cooperative Medical Sciences program and
through the Public Law 480 foreign currency program using
U.S. -owned local currencies derived from the sale of surplus
agricultural commodities in developing countries. Only
half the earth's population maintains an adequate diet,
indicating a critical need for research to find techno-
logic ways and means to transform marginal nutrition and
overt nutrition deficiency to adequacy.
Traditionally, the National Institute of Arthritis,
Metabolism, and Digestive Diseases has conducted nutrition
research in developing countries because of the availability
of large population groups afflicted with specific
nutritional deficiences that can be readily studied. The
results from such research are twofold: It may stimulate
emergence to self-sufficiency from mere subsistence in
Southeast Asian countries, as well as add to knowledge
concerning normal nutrition and nutritional requirements
that will benefit the U.S. population.
The startling realization that malnutrition can,
in fact, exist within our own population lends an element
of expediency to nutrition research. By providing scienti-
fic .know-how for effective utilization of economical,
indigenous protein sources, these programs also discourage
dependency of developing countries on the United States
for provision of expensive protein-rich foods and enable
them to make inroads against endemic protein malnutrition.
The mission of the malnutrition segment of NIH's
U.S. -Japan Cooperative Medical Sciences program is to
support both basic and applied research aimed at practical
solutions to nutrition-related problems in the countries
of South East Asia and other nations in the Pacific area.
The substantial grant and contract program has already
brought about significant findings that will help to
improve the protein level of rice, the principal food of
60 percent of mankind. Ordinary commercial rice lacks
sufficient protein for normal growth and development of
children maintained on a predominantly rice diet; in
addition, it does not protect the adult population from
serious protein undernutrition.
Research identified approximately 100 rare rice
varieties that contain from 13 to 17 percent protein in
contrast to the conventional level of 7 1/2 percent in
102
currently available commercial rice varieties, A
vigorous plant breeding program has been started with the
aim to develop a variety of high-protein rice that has all
the necessary additional qualities (such as disease resist-
ance, high yield per acre, identical taste and mouth-feel
as conventional rice) that would make possible and
commercially feasible large-scale planting and distribu-
tion of high-protein rice.
In the future, however, because of a change in the
protocols of the U.S. -Japan program, the agricultural
portion will no longer be .supported by NIH funds. While
the human nutrition aspects of this project will continue
under the auspices of NIAMDD, the International Rice
Research Institute in Los Banos, Philippines, has assumed
responsibility for agricultural experimentation.
Studies of the distribution, importance, and methods
of control or elimination of natural toxic substances in
legumes and other plant foods focused primarily on the
distribution of mycotoxin in the food supply of Asian
countries and its relation to human disease. The principal
work, supported by a contract with Drs. Gerald Wogan and
Ronald Shank of the Massachusetts Institute of Technology,
has now been concluded. Their studies resulted in the
publication of 15 scientific papers documenting the
widespread occurence of aflatoxin and other mold toxins
in Asian foods and their probable association with liver
damage in those who habitually consume foods contaminated
with such toxins.
The investment in a large nutritional research
center in Chiang Mai, Thailand, has yielded a significant
amount of data in two priority areas of the U.S. -Japan
program — nutritional anemia and interactions of malnutri-
tion and infections. In studies by center personnel,
almost 80 percent of the more than 1,500 children attending
the hospital ' s outpatient department were found to be
iron deficient and responded completely to iron therapy.
In a companion study, 3,2 30 pregnant women were surveyed
for hematologic status: 70 percent were iron deficient;
20 percent, folic acid deficient; and 13 percent had
combined deficiencies. Of particular interest was one
case of pernicious (Addisonian) anemia discovered during
the study — the first reported in a Thai.
The latest study reported from Chiang Mai explored
the role of varying amounts of protein and calories on
the hematologic responsiveness of children with protein-
calorie malnutrition (PCM) . In this investigation, the
addition of protein and calories elicited a therapeutic
response, with protein recording the greater effect.
Part of this action is thought to be related to the
responsiveness of erythropoietin (a glycoprotein considered
103
to be the humoral plasma factor that stimulates red cell
production in the bone marrow) to protein feeding.
Bladder Stone Disease in Thailand
Bladder stone disease is one of the most serious
health problems in northern Thailand, occurring primarily
among village children 5 years of age and under. Research
by NIAMDD grantees Drs. Aree Valyasevi and Sakorn
Dhanamitta indicates that oxalcrystalluria (excessive
amounts of crystalline oxalic acid salts in the urine)
was commonly found in urine samples of villagers, but
only rarely in specimens of city dwellers. Moreover,
calcium oxalate was shown to be one of the main constituents
of the urinary stones.
A dietary survey showed that the villagers daily
consumed several kinds of local vegetables and leaves of
forest plants not eaten by the townspeople. Further
study revealed that these food items such as tampala
and bamboo shoots were high in oxalic acid content, possibly
leading to the heavy oxalcrystalluria and crystal clumping,
particularly among children.
To counteract this occurrence, the investigators at
Ramathibodi Hospital in Bangkok administered oral doses
of orthophosphate, which eliminated almost all crystalluria
and crystal clumping in the patients studied.
The researchers concluded that in all future studies
on the origin of bladder stone disease, external sources
of oxalic acid (which heretofore had not received as
much attention as the possibility of metabolic abnormali-
ties) should be an important consideration.
NATIONAL INSTITUTE
OF
CHILD HEALTH AND HUMAN DEVELOPMENT
Nutrition
The National Institute of Child Health and Human
Development (NICHD) is conducting a series of coordinated
studies on nutrition and mental development. The largest
of these is a contract-supported study begun in 1964 in
cooperation with the Institute of Nutrition of Central
America and Panama and the Pan American Health Organization.
The data from four small rural villages in Guatemala
indicate that consumption of a dietary supplement by under-
nourished pregnant women may increase birth weight of
babies to approximately the birth weight observed in more
favored populations. Infant mortality also has been
reduced by this supplementation. Preliminary data suggest
there may also be some beneficial effects on early be-
havioral development.
In a smaller grant-supported study under way at the
Institute for Mother and Child in Mexico, food supplemen-
tation of the mother and infant has greatly increased the
level of activity and alertness of the infant. In addition,
it has increased the interaction between the mother and
her child.
Two other projects are under way in Colombia in
cooperation with U.S. universities. The first utilizes
regularly available food items to improve the diet of
pregnant women or children in urban Bogota. The Colombian
Institute of Nutrition specialists and scientists from
Harvard University are seeking to determine when the
supplementation program should be introduced in order to
effect optimal changes in growth, health, and behavior
of the offspring. The second Colombian project is under
the direction of a research team from Northwestern
University and the Universidad del Valle in Cali, Colombia.
These studies focus on undernourished preschool children.
The data suggest that both nutrition intervention and an
educational stimulation program may be necessary to over-
come the deleterious effects of early malnutrition.
Still another project is under way through the
University of Santiago, Chile. This study is seeking to
clarify the complex interrelationships among malnutrition,
maternal IQ, and other social variables that influence a
child's mental development.
Using money allocated from the U.S. -Japan Cooperative
Medical Science program, another NICHD joint project with
105
106
the Institute of Nutrition of Central America and Panama,
consisted of a 9 year longitudinal study of nutrition,
infection, and growth among pregnant and lactating women,
infants, and children of a small native village in
Guatemala. A monograph summarizing these findings will
soon be published.
Another joint NICHD-Institute of Nutrition of Central
America and Panama project consists of two concurrent
studies on the ecology of infection, malnutrition, and
growth of children in two Guatemalan Indian villages.
One study seeks to determine whether the antibacterial
defenses of the newborn are influenced by maternal nu-
trition status, birthweight, and general health status
of the infant. The second study is assessing the ability
of malnourished children to elicit and maintain appro-
priate humoral antibody response to measles vaccine and
natural measles infection. An ongoing project funded by
the Office of Nutrition of the Agency of International
Development provides nutritional supplementation to the
families of one village; a second village serves as a
control .
Population Research
The Center for Population Research (CPR) of the NICHD
has several important contracts and grants with insti-
tutions outside the United States, some of which are des-
cribed here. As part of its efforts to develop a variety
of safe and effective contraceptive methods for both men
and women, CPR supports studies at Laval University,
Montreal, Quebec, Canada, to synthesize chemical analogs
of steroidal antifertility compounds and in an effort
to identify the chemical factor in the testicles that
regulates spermatogenesis, CPR has contracted with the
University of Trondheim, Norway.
Under contract from the CPR the Medical Information
Center at the Karolinska Institutet, Stockholm, Sweden,
supplements and enhances bibliographic data available
through the National Library of Medicine in the biological
and medical fields relevant to human reproduction. The
Human Reproduction Thesaurus produced by the center includes
citations to journal articles, technical reports, mono-
graphs, and symposia not previously included.
As part of its program to evaluate the long-term
effects of vasectomy, the CPR has contracted with the
Netherlands Cancer Institute, Amsterdam, to study human
sperm antigens and the development of antibodies in
naturally infertile and vasectomized men. A new antigen
from human sperm, the "swollen sperm head antigen," has
been demonstrated in sera of vasectomized men, and its
possible medical significance is being investigated.
107
To evaluate the effect of oral and other contracep-
tives on congenital abnormalities and outcome of pregnancy,
a research project is being supported with the Hebrew
University-Hadassah Medical School in Jerusalem, Israel.
This study will measure the effects of contraceptives used
prior to and at the time of conception on outcome of
pregnancy, especially the incidence of congenital defects
and chromosome aberrations.
A contract with the Mario Negri Institute of Phar-
macological Research in Milan, Italy, supports a wide
range of studies of the effects of currently used contra-
ceptive steroids in laboratory animals. This project is
part of a program designed to define better animal models
for predicting possible adverse reactions to these agents
in women .
In the behavioral sciences, a grantee at the Hebrew
University, Jerusalem, Israel, is studying the conditions
that affect fertility patterns in Israel among Arab and
Jewish populations.
Another project in the behavioral sciences is analyzing
census and national longitudinal survey data to determine
the relationship between urbanization/migration and fer-
tility in Thailand. The high fertility and low mortality
characterizing Thailand place its population among the
fastest growing in the world. In analyzing such data
this study will add another perspective to the under-
standing of influences upon fertility behavior.
Remedial Learning
Under a grant from the NICHD, a team of investigators
in Israel have developed a highly successful and innovative
program that has significantly improved the mental per-
formance and learning skills in adolescent, low-functioning
immigrant children from markedly disadvantaged cultural
backgrounds. Departing from standardized intelligence
tests and question-and-answer methods as an assessment
device, the investigator has developed a "learning poten-
tial assessment device" in which the tester trains the
child to learn principles underlying problems - to make
analogies and inferences. Through this dynamic inter-
vention process, the child overcomes deficient ways of
functioning and his progress offers diagnostic insights
into how much he can be helped.
Once the child's potential has been ascertained, he
begins a system of carefully graded exercises (instrumental
enrichment) designed to stimulate his curiosity, to enable
him to compare different aspects of his environment,
and to categorize and think about his behavior. By
contrast, teaching techniques in the United States for
108
children with learning disabilities are concentrated
primarily on the learning of skills and transmission of
knowledge.
This approach has been widely adopted with remarkable
success by the Israeli school system and in special mili-
tary training units for illiterate and educationally
retarded youth. Although data are not yet fully reported,
hundreds of disadvantaged youths have successfully com-
pleted school and gone on to lead useful, constructive
lives. Through a series of seminars, American and Canadian
scientists are beginning to apply and test these techniques
in their own research facilities and classrooms.
This project is now in its final year of operation
and data analysis. The investigator is near completion
of a manuscript for book publication (in the United States)
in which the theoretical rationale underlying his diag-
nostic and intervention methods and instrumentation will
be elaborated for application in this and other cultures.
There is a strong possibility that the techniques developed
in this project could have direct relevance to seriously
disadvantaged populations in the United States.
Sudden Infant Death Syndrome
The NICHD is supporting three foreign studies of the
sudden infant death syndrome (SIDS) . An animal model for
the study of SIDS is being developed at the Nuffield In-
stitute for Medical Research, University of Oxford, England.
The Oxford investigators had previously found that certain
liquids, such as water, sugar water, cow's milk, human
and artificial milks, would trigger apnea (periods of
nonbreathing) in newborn lambs. Under contract with the
NICHD, these investigators are studying how the larynx
and its nervous control may relate to the arrest of
breathing in fetal and newborn lambs and kittens ; parti-
cularly, what effects do fluids such as water (with and
without sugar) and milk have on closure of the upper air-
way? So far the investigators have found that at a certain
stage in development kittens are more vulnerable to the
fluid stimulus. They have identified two nerve receptor
areas in the upper airway of the kittens that seem to be
involved in the fluid-triggered apnea response.
Pursuing a lead that SIDS may result from inadequate
lung responses, a grant-supported study at the Hospital
for Sick Children in Toronto, Canada, is exploring the
hypothesis that some infants' lungs cannot respond to
stress on their respiratory system and that this might
contribute to the occurrence of SIDS. A Canadian scientist
is taking measurements of breathing activity, such as
mouth pressure, lung capacity, and frequency of inspiration/
expiration in newborn and older infants. Calculations with
109
these data should produce a method of measuring the elas-
ticity and strength of the respiratory system of the newly
born and young infant.
A contract with the University of Toronto, Canada,
supports studies to characterize the effects of respira-
tory tract sensory feedback on the respiratory behavior
of adult cats and kittens. A particularly striking
observation has been that the activity of only 50 percent
of the rhythmically active neurons in the adult could be
suppressed by peripheral sensory feedback, while the
discharge of all similar cells so far tested in the kitten
was suppressed. Differences have also been found in
excitory input between the adult and infant animals. These
preliminary findings that the suppressive effect of the
upper airway feedback on ventilation is greater in young
animals appear highly relevant to the etiology of SIDS.
Processes Basic to Reading
The NICHD currently supports an unusually interesting
and potentially important study in the basic reading
processes in Yugoslavia. A number of different experiences
are being conducted that focus on the basic information-
processing steps involved in letter and word recognition.
These experiments take advantage of the fact that Serbo-
Croatian, the language of Yugoslavia, uses two ortho-
graphies (alphabets) ; both the Cyrillic and the Roman
alphabets are entirely phonetic and each is read with
equal facility by many Yugoslavs. The research exploits
this situation, making possible detailed comparisons with
similar studies conducted with English speakers at U.S.-
based laboratories under TSIICHD support. The emphasis in
this research is on the units of recoding from visual to
phonetic form and on the linguistic level at which visual
inputs merge into the processes of speech. For example,
in one experiment subjects are shown successive tachisto-
scopic (flash projector) presentations of letters (Roman-
Roman, Roman-Cyrillic, etc., a procedure designed to
create a masking effect; subjects must attempt to identify
the letters. The institute anticipates significant, new
information from studies of this type that will lead to
a better understanding of the normal reading process and
those factors that interfere with or prevent many children
from acquiring this essential skill.
NATIONAL INSTITUTE
OF
ENVIRONMENTAL HEALTH SCIENCES
U.S.-U.S.S.R. Medical Science and
Public Health Cooperative Agreement
Under the public health part of the U.S.-U.S.S.R. Coop-
erative Health Agreement, NIEHS and several other American
research institutes have developed a collaborative research
program with several Soviet scientific institutes to
explore three problem areas in environmental health: the
methodologic basis to assess the biologic effects of in-
haled chemicals; the methodologic basis to assess the bio-
logic effects of orally introduced chemicals; and the
scientific basis to assess the complex biologic effects
of chemicals inhaled and introduced orally. These three
problem areas are subdivided into eight specific research
subjects. U.S. participation in this effort is under the
overall coordination of the director, NIEHS.
1975 was the third year of formal cooperative efforts
in environmental health between the United States and
U.S.S.R. The first year was concerned largely with estab-
lishing working relationships and agreeing on areas of
joint study. Initiation of joint research efforts began
in the second year of the agreement and involved exchange
visits between scientists of both sides.
In December 1974, U.S. and Soviet researchers partici-
pating in the agreement met at the invitation of the Soviet
government in Riga, Latvia, to present the results of
their cooperative effort to date. Five NIEHS scientists
attended this meeting. The results of this symposium will
be published in 1975 in both the United States and the
Soviet Union. A cooperative research program for 1975-1976
was agreed upon during the Riga symposium.
By the end of 1975, over 20 scientific papers will have
been published by U.S. and Soviet scientists on environ-
mental health research conducted under the auspices of
this agreement.
An initial draft of a Russian-English glossary of en-
vironmental health terms was prepared during 1974 and is
currently under review by both countries. A first edition
of this glossary will be published in 1975 in both countries
111
112
U t S."U.S,S.R t Agreement on Cooperation
in the
Field of Environmental Protection
NIEHS participation in this agreement, which spans
the most significant aspects of problems of the environment,
is focused on the area of the "biologic and genetic
effects of pollutants." The director, NIEHS, serves as
HEW representative to the Environmental Protection Agree-
ment and as co-chairman of the working group for the problem
area concerned with the biologic and genetic effects of
pollutants. Cooperation in this area, involving scientists
from NIEHS, EPA, and university laboratories, is focused
on the mutagenicity of environmental contaminants, the
toxic effect of heavy metals in the environment, psycho-
physiologic factors, and epidemiology. Program activity
in 1975 consisted largely of information exchange and a
joint workshop in New York City in April on "Basic and
Practical Approaches to Environmental Mutagenesis and
Carcinogenesis. "
Investigation of Inhaled Pollutants
under the U.S. -French Agreement
for Scientific Cooperation
In fulfilling its responsibilities under the agreement
reached between NIH and the Institut National de la Sante
et de la Recherche Medicale (INSERM) in May 1970, the
National Institute of Environmental Health Sciences
sponsored Dr. N. LeRoy Lapp, Appalachian Laboratory for
Occupational Respiratory Diseases, NIOSH, during his ex-
change visit to Dr. Sadoul's laboratory in Nancy, France,
from September through December 1974.
NIEHS has reviewed its participation in the program
and has recommended that further participation by NIEHS
be discontinued with the proviso that in the future, as
priorities and resources allowed, NIEHS would again like
to be an active participant.
U.S. -Japan Cooperative Medical
Science Program
Dr. Charles Langley, Environmental Mutagenesis Branch,
NIEHS, attended the Third Joint Conference of the Panel
on Methods for Evaluating Environmental Mutagenesis and
Carcinogenesis in Tokyo, Japan, August 1974.
113
Cooperation with the
World Health Organization
NIEHS has continued its cooperation with WHO in several
activities. Dr. Hans L. Falk, Associate Director for
Program, NIEHS, attended the first WHO conference on the
"Assessment of Potential Health Hazards from Technological
Developments," held in Geneva, September 1974. Dr. Falk
is involved in preparing a follow-up series of inter-
national conferences, sponsored jointly by WHO and NIEHS,
on health hazards resulting from established or newly
developed technologies. The first of these conferences,
dealing with the rubber and plastics industries, will be
held at NIEHS during fiscal 1976.
A WHO program to prepare international health criteria
documents on important environmental pollutants has pro-
duced over a dozen documents that have been directed to
NIEHS for comment and evaluation.
Dr. Falk has been involved in the planning of a manual
on the evaluation of the toxicity of chemicals, including
the preparation of a chapter on modifying factors, mech-
anisms of potentiation, and antagonism, for completion in
early 1976.
Dr. Falk represented WHO at the meeting on "Impact of
Production and Use of Energy on the Environment" sponsored
by the United Nations Environmental Program (UNEP) in
New York, February 19 75.
Dr. Robert L. Dixon, Chief, Environmental Toxicology
Branch, NIEHS, met with the task group of the WHO Expanded
Programme of Research, Development and Research Training
in Human Reproduction in Geneva during November 1974 for
the review of applications for research grants. Dr. Dixon
also participated in the WHO/FDA coordination of toxicology
guidelines for intracervical devices in January 1975.
Dr. Robert E. Staples, Environmental Toxicology Branch,
NIEHS, attended a meeting of the WHO Teratology Task Group
in London during January 1975 to discuss teratology of
medicated and nonmedicated IUDs.
Drs. H. V. Mailing and George Mohn, Environmental Mu-
tagenesis Branch, NIEHS, participated as members of a
working group on the "Evaluation of Carcinogenic Risk of
Chemicals to Man" in Lyon, France, April 19 75.
To facilitate further cooperation between NIEHS and WHO,
the WHO has begun to take the necessary steps toward
officially naming NIEHS a WHO cooperating center.
114
In cooperation with the International Agency for Research
on Cancer (IARC, Lyon, France, a sister organization of
WHO) , Dr. Falk has been involved in the preparation of
monographs on the evaluation of carcinogenic risk of
chemicals to man. Dr. Falk has prepared background doc-
uments on four chemicals and their derivatives : asiati-
coside, cantharidin, carrageenans , and cholesterol.
Seminars Sponsored by NIEHS
Dr. F. Oesch, Department of Pharmacology, University
of Basle, Switzerland, presented a seminar entitled,
"Epoxide Hydrases : Inducible Enzymes Involved in the
Inactivation of Carcinogenic and Cytotoxic Metabolites
Derived from Aromatic Olefinic Compounds," July 1974.
Dr. H. Uehleke, Institute of Pharmacology, University
of Tubingen, West Germany, presented a seminar entitled,
"The Metabolism of Haloalkanes and Their Covalent Binding
to Tissue Macromolecules , " August 19 74.
Dr. B. Ketterer, Middlesex Hospital Medical School,
London, England, presented a seminar entitled, "Studies
of Ligandin and Glutathione-S-Aryl Transferase Activity
in Rat Liver Cytosol," September 1974.
Professor P. Armitage (London School of Hygiene and
Tropical Medicine), Dr. P. Lee (Tobacco Research Council
Labs, England), and Dr. R. Peto (Oxford University, England)
made presentations at the NIEHS Wrightsville Beach Con-
ference on "Extrapolation of Risks to Man from Environ-
mental Toxicants on the Basis of Animal Experiments," held
at Wrightsville Beach, North Carolina, September 1974.
Dr. M. Ahmad, Institute of Biology, Islamabad, Pakistan,
presented a seminar entitled, "A Trystophanyl tRNA
Synthetase Mutant in Neurospora crassa , " October 1974.
Professor C. Rappe , Department of Chemistry, University
of Umea, Sweden, presented a seminar entitled, "Environ-
mental Chemistry of Some Chlorinated Hydrocarbons, November
1974.
Dr. G. M. Holder, University of Sydney, Australia, pre-
sented a seminar entitled, " In Vitro Metabolic Studies of
Benzo(a) pyrene in Rat and Mouse by Liquid Chromatography,"
November 197 4.
Dr. B. Charlesworth, University of Sussex, England,
presented a seminar and discussed research programs,
February 197 5.
115
Dr. D. V. Parke, Department of Biochemistry, University
of Surrey, Guildford, England, presented a seminar entitled,
"Recent Developments on Biphenyl Hydroxylation as a Model
Enzyme System for Monitoring Carcinogens," March 1975.
Dr. T. Matsushima, National Cancer Center Research
Institute, Tokyo, Japan, presented a seminar entitled,
"Effects of Microbial Protease Inhibitors on Carcino-
genesis and Metastasis," March 1975.
Dr. E. Evans, Sir William Dunn School of Pathology,
Oxford, England, presented a seminar on "The Cytogenetics
of Inversions in Mice," March 1975.
Eight foreign scientists participated in the workshop
to discuss international coordination of research in
environmental mutagenesis, May 1975: Dr. C. Ramel,
University of Stockholm, Sweden; Dr. P. Oftedal, University
of Oslo, Norway; Dr. Y. Tazima, National Institute of
Genetics, Sizouka-Ken, Japan; Dr. B. Bridges, University
of Sussex, Brighton, England; Dr. N. Loprieno, Institute
of Genetics, Pisa, Italy; Dr. U. Ehling, Institute for
Biology, Munich, West Germany; Dr. K. Sundaram, Bhabha
Atomic Research Center, Bombay, India; Dr. H. Boehme ,
Inst. Fuer Kultur-Pf lazenforschung , Gatersleben, East
Germany.
Dr. R. Fahrig, Central Laboratory for Mutagenesis,
Freiburg, West Germany, presented a seminar entitled,
"A Mammalian Mutagenicity Spot Test: Induction of Genetic
Alterations in Pigment Cells of Mouse Embryos with X-Rays
and Chemical Mutagens," May 1975.
Dr. W. Muller, Bielefeld University, West
Germany, presented a seminar entitled, "Base and Sequence
Specificity of DNA-Complexing Agents," June 1975.
International Visits of NIEHS Staff
July 1974
Dr. J. McKinney presented a paper at the Third Inter-
national Congress of Pesticide Chemistry in Helsinki,
Finland. Dr. McKinney also visited the laboratories of
Dr. G. T. Brooks, University of Sussex, England, to
discuss mutual research interests.
Drs. F. Andrew and R. Staples attended the annual
meeting of the Teratology Society in Vancouver, Canada.
Dr. F. de Serres met with Dr. Stitch in Vancouver,
Canada, to discuss marine research.
116
August 1974
Seven scientists from the NIEHS Pharmacology Branch
presented papers at the Pharmacology Society Fall Meeting
in Montreal, Canada.
Dr. D. Hoel attended the Eighth International Biometric
Conference in Constanta, Romania.
Drs. R. Maurer, J. McLachlan, and R. Staples attended
a meeting of the Society for the Study of Reproduction
in Ottawa, Canada.
NIEHS sponsored a trip by Drs. Roy Albert and Bernard
Goldstein to Moscow, U.S.S.R., to participate in the U.S.-
U.S.S.R. Environmental Health Agreement.
September 1974
Dr. W. Sheridan traveled to Stockholm, Sweden, and
Munich, West Germany, for discussions with mutagenic
researchers.
Dr. L. Valcovic traveled to Munich and Uppsala, West
Germany, to discuss current research programs and to
present seminars.
October 1974
Drs. F. de Serres, W. Jurgelsky, and M. Lieberman
attended the XI International Cancer Congress in Florence,
Italy.
Dr. E. Soares traveled to Toronto, Canada, for con-
tinuation of collaborative research efforts with Dr. Bruce,
Drs. Rail, Dixon, Gardner, Schambra, Staples, Drew,
and Ms. Lange traveled to Moscow, U.S.S.R., to participate
in the U.S.-U.S.S.R. Environmental Health Agreement.
April 1975
Dr. H. Mailing visited the Department of Genetics,
University of Edinburgh, Scotland, and the Radiation and
Environmental Hazard Research Laboratory, Munich, West
Germany.
Dr. H. Falk met with a group of experts concerned
with marine pollution in London, England.
117
May 1975
Drs. J. Fouts and J. Bend visited with Dr. Stitch in
Vancouver, Canada, to discuss mutual research concerns.
Drs. G. Hook and J. Crapo attended an international
conference on lung diseases in Montreal, Canada.
Dr. F. de Serres participated in the International
Symposium on Genetic Hazards to Man from Environmental
Agents in Ottawa, Canada.
Dr. C. Langley presented a paper at the Symposium on
Human Population Monitoring methods for Detecting In-
creased Mutation Rates in Freiburg, West Germany, and
visited laboratories in England and Denmark.
Dr. J. Woods attended the First International Porphyrins
Meeting in Freiburg, West Germany.
Dr. D. McRee attended the International Microwave
Power Symposium and the American National Standards In-
stitute meeting in Waterloo, Canada.
Drs. Lucier, McLachlan, and Schambra traveled to Moscow,
U.S.S.R. to participate in the U.S.-U.S.S.R. Environmental
Health Agreement
June 1975
Drs. D. Rail, F. de Serres, G. Lucier, and J. McLachlan
attended the joint meeting of the European Society of
Toxicology and the U.S. Society of Toxicology in Mont-
pellier, France. Dr. de Serres also traveled to Brussels,
Belgium, to attend a workshop on rapid screening tests to
predict late toxic effects of environmental chemicals and
to Paris, France, to participate in a conference "From
Molecular Recognition to Perception." Drs. Lucier and
McLachlan also visited research laboratories in Stockholm
and Lund, Sweden.
Dr. R. Drew attended an international conference
"Radioactive Anomalies and Their Biological Implications,"
Pocos de Calda, Minas Gerais, Brazil.
International Visitors to NIEHS
Dr. G. Rentsch, Professor of Pharmacology, University
of Heidelberg, and Research Director, Toxicology Research,
Sandoz Ltd., Basle, Switzerland, was a guest of Drs. Hook
and Fouts. While here, he discussed research with various
branch scientists, gave an informal seminar, and demonstrated
a technique for animal whole body perfusion (July 1974) .
118
Dr. Drew described aerotoxicology programs and showed
the inhalation facilities to Dr. Komal , Undersecretary
of State for Public Health, Thailand, and Dr. Sonchai ,
Director of the Thailand National Cancer Institute (August
1974) .
Dr. S. S. Parmer from India and currently visiting
professor, Department of Physiology and Pharmacology,
University of North Dakota, visited the Pharmacology
Branch as a guest of Dr. Chhabra and discussed research
with various branch scientists (September 1974) .
Drs. Fouts and Drew met with Dr. C. Szymezykiewicy ,
Director of the Institute of Medicine in Mining and Metal-
lurgical Industries, Zabrze, Poland, and discussed branch
research and mutual interests in solvent toxicity and
aerosol toxicology (September 1974) .
Dr. Hart hosted a visit by Dr. Justyna Wisnieska-Knypl ,
Lodz, Poland. Dr. Wisnieska-Knypl discussed research
programs, visited several branch laboratories, and learned
liver perfusion techniques while here (November 1974) .
Professor Christoffer Rappe , Department of Chemistry,
University of Umea, Sweden, visited Dr. J. D. McKinney at
NIEHS for research discussions on chlorinated hydrocarbon
chemistry (November 1974) .
Dr. Drew discussed animal and human exposures and vapor
detectors with Dr. Lars Moelhave, Denmark (January 1975).
Dr. Agthe of the International Agency for Research on
Cancer, Lyon, France, met with Dr. Falk to discuss common
interests and problems regarding the preparation of IARC
monographs (January 19 75) .
Dr. Preussmann, Heidelberg, Germany, visited NIEHS to
discuss problems in assessment of carcinogenicity of
chemicals with Dr. Falk (February 1975).
Drs. U. A. Kuzminskaya and L. V. Marston of the All-
Union Institute of Hygiene and Toxicology of Pesticides,
Polymers and Plastics, of Kiev, U.S.S.R., discussed with
Dr. Hart possible collaborative activities with Russian
counterparts in pharmacokinetics; with Drs. Hart and Eling
they discussed programs on PCB pharmacokinetics and lung
accumulation of xenobiotics. Dr. Drew talked with them
about the technology of inhalation exposures. Dr. Fouts
discussed with them induction of mixed-function oxidases
(MFOs) by pesticides and the best tests for induction in
humans and provided them with bibliography and reprints of
selected papers on human screening tests for MFO induction
by pesticides (February-March 1975) .
119
Dr. Hart described branch research programs for Dr. R.
Preussmann, Institute for Experimental Tumor Production
and Tumor Treatment, Heidelberg, West Germany (February
1975) .
Dr. D. V. Parke, Department of Biochemistry, University
of Surrey, Guildford, England, discussed with Dr. Fouts ,
U.S. -U.K. cooperative programs in environmental health
sciences (March 1975) .
Dr. Drew discussed aerotoxicology facilities and studies
with Dr. E. Poulsen, Director, Institute of Toxicology,
Denmark (March 1975) .
Dr. Bernard Matter, Biological and Medical Research
Division, Sandoz Ltd., Basle, Switzerland, met with members
of the Microbial and Plant Genetics Section to discuss
the micronuclei test systems for detecting mutagenicity
of environmental agents (May 1975) .
NATIONAL LIBRARY OF MEDICINE
The National Library of Medicine (NLM) continued its
international relationships which are based primarily on
cooperative and sharing arrangements. The international
character of the biomedical literature is illustrated
by the fact that appoximately 64% of the 20,000 bio-
medical periodicals acquired by NLM annually are non-
U.S. From this massive amount of material, NLM has
selected with the aid of consultants, 2,300 biomedical
journals which form the corpus of our computerized
activity, MEDLARS/MEDLINE, and our published Index
Medicus .
The Library has received many non-U. S. requests for
the MEDLARS data base or for the services originating
from it. Such requests were received even before the
system became operational in 1964, and often from a
number of institutions in the same country, all wishing
to be designated as a MEDLARS center.
A primary and continuing NLM decision throughout
the years has been that any international arrangements
relating to the MEDLARS system should be based on
substantive technical cooperation. Today, the Library
has eight bilateral arrangements with Australia, Canada,
France, Germany, Japan, Sweden, the United Kingdom, and the
World Health Organization. Table I shows their period
of operation. These arrangements represent a sharing of
time, talent, and resources with no transfer of funds.
In return for access to the MEDLARS system, the partici-
pating country agrees to provide: MEDLARS services to'
its biomedical community; a document support service;
indexed input to the NLM's MEDLARS system; and to pay
for personnel sent to NLM for training in indexing and
searching.
The administrative setting for these MEDLARS centers
varies from country . to country. The National Library
of Medicine has maintained a policy of requiring the
participating country to select the institution from
among the many who have requested being a MEDLARS center.
Thus, the MEDLARS center may be in an organization
which is primarily concerned with medicine or health; a
library; or an organization devoted broadly to science
and technology. In each case, however, the center has
been given a national mandate to serve the country.
(Table II)
It was envisaged that a unique role could be performed
by the World Health Organization in providing service,
121
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124
not only to its Technical Staff and Commissions, but to
the developing countries that would receive information
not available under other mechanisms of national
auspices. WHO is in the early phases of this activity.
The current NLM bilateral arrangements reflect
MEDLARS II developments. A meeting of the International
MEDLARS Policy Advisory Committee was held in November
1975. This was the third such meeting of Policy Officials,
accompanied by the Directors of the MEDLARS Centers.
It reexamined the cooperative efforts, operational
experience, regional coverage, networking, the availa-
bility of TOXLINE/CHEMLINE and future collaboration.
Exchange Programs
Through the years the Library has developed coopera-
tive exchanges and these now number 895 exchange partners
in 85 countries throughout the world. This is a
mechanism for acquiring material which may not be
otherwise readily obtained. The program has been under
review this year to ensure that there is an equivalence
to the material being exchanged.
The People's Republic of China is now an integral
part of this exchange program and the Library receives
five Chinese medical journals. This is in contrast
to the 91 Chinese journals, including 30 major medical
periodicals, which had been published and received
prior to 1966.
Aid Services
The Library continues to provide services to
developing countries under a special arrangement with
the U.S. Agency for International Development. About
20,000 such services are provided each year to 48
developing countries throughout the world. The geographic
distribution is estimated to be 29 percent to Latin
America, 60.8 percent to the Near East, 8.3 percent to
the Far East and 1.9 percent to Africa. This assistance
responds to a demonstrated need in countries where there
are insufficient medical literature resources. The
services include interlibrary loans, reference requests,
MEDLINE searches, loan of audiovisual materials, and
subscriptions to Index Medicus and Abridged Index Medicus .
Many aspects of medical research, education, public
health and preventive medicine are encompassed in these
services. The level of activity made possible by this
NLM/AID agreement, however, does .iot respond totally to
all needs of the developing nations.
125
Public Law 480 Programs
About $10,000,000 equivalent in foreign currencies
of seven countries has been obligated to date for the
over-all program. At present, NLM sponsors projects
in Poland, Israel, Yugoslavia, Tunisia, Egypt, India
and Pakistan, including analytic critical reviews
and biomedical monographs, histories of medicine,
secondary literature tools in the health sciences (such
as guides, atlases, handbooks), translations of current
and historical foreign biomedical monographs and proceed-
ings of international conferences. There is collaboration
with major U.S. scientific societies, both to determine
the need for studies in special biomedical areas, as well
as to arrange for distribution in the United States.
University presses and professional societies, as well
as the National Technical Information Service, are
utilized in the dissemination of studies funded under
the Library's PL 480 program.
During Fiscal Year 1975 the Library's Special
Foreign Currency Program numbered 110 active projects
in the seven participating countries, of which 10 were
new projects. These were a monograph on the "Organization
of Health Care" in Poland, a review of "Tuberculosis of
the Spine" in India, a translation of a Russian monograph
on "Brain and Activation," five critical reviews, and
publication of two conference proceedings on enivronmental
physiology and on diabetes and metabolite endocrinology.
(Table III) About 70 percent of the program (primarily
critical reviews) is prepared in Poland and Israel, with
the remainder (largely translations) carried out in
Tunisia, Egypt, India and Pakistan. During FY 1975
sixteen publications resulting from PL 480 support were
received.
Foreign Visitors
The Library receives more than 1,000 visitors
annually from other countries - physicians, medical
librarians and information specialists. In furthering
the exchange of information and ideas, the Library
arranges special programs for these visitors consistent
with their professional responsibilities. Of concern to
the many visitors to the Library were topics such as the
concept of a national biomedical information resource;
specialized information activities in cancer, cardio-
vascular diseases and toxicology; health care and computer
aided instruction. There were numerous study teams
which included groups from Japan, Sweden, Pakistan,
Germany, Algeria, U.S.S.R., Iran, Mexico, Trinidad and Tobago,
and Egypt.
126
In Januaxy 1975 Dr. O.K. Harlem was appointed as a
Visiting Scientist at the National Library of Medicine
for one year. Dr. Harlem is a specialist in pediatrics,
has been a general practitioner, a hospital physician,
a university teacher and an editor. Dr. Harlem's
contributions are in both the substance of medicine and
in the communications and publication of biomedical
information. He is developing a monograph during his
stay at the National Library of Medicine which will form
the basis of a course in biomedical communications
within a medical school curriculum.
National Biomedical Information Centers
The National Library of Medicine, functioning as
a national biomedical information resource, has attracted
the interest of a number of governments who have expressed
interest in establishing national biomedical information
centers. The NLM does try to assist on a technical
consultation basis. Although it does not provide foreign
fellowships or have a formal training program, it is
responsive to requests for the specialized training of
physicians and information specialists who have been
designated to direct a national information activity in
their own country.
Two specific arrangements have developed with
Egypt and Iran. In October 1974 the Assistant Secretary
for Health, HEW, and the Minister of Health of Egypt
held a U.S. -Egyptian Joint Working Group meeting on Medical
Cooperation. As a direct result of this meeting, the
Chairman of the Board of Regents of NLM and the Library's
Assistant Director for International Programs met with
Egyptian officials to discuss potential collaboration in
biomedical information. In July 1975 the second meeting
of the full Joint Working Group met in Washington, D.C.,
at which time the Assistant Secretary, HEW, and the
Minister of Health of Egypt agreed that both parties
recognize that biomedical information is a necessary
component of biomedical research, education and the
delivery of health services. It was also agreed to explore
cooperative arrangements which will result in improved
biomedical communications between and within both countries.
In particular, experiences will be shared which relate to
the development of a national biomedical information resource
and an operational national medical library system.
At the request of the Minister of Science and Higher
Education of Iran, the NLM has assisted in the planning
of a national medical library and also in determining
what bilateral cooperative relationships could be developed
between the Imperial Medical Center of Iran and the U.S.
National Library of Medicine. As a result, Iran is in the
early stages of developing a national medical library and
127
information resource. On May 12 f 1975 the Director of the
National Library of Medicine and the Minister of Science
and Higher Education of Iran signed a Memorandum of
Understanding under which NLM will provide technical
consultation, training and specialized services as
requested and funded by Iran.
Regional Programs for Biomedical
Information
The regional approach taken by the Pan American
Health Organization (PAHO) in its establishment of a
Regional Library of Medicine (BIREME) in Sao Paulo,
Brazil in 1967 has resulted in an effective operational
activity. The NLM serves as a technical consultant
and backstop to PAHO and BIREME.
Since its first full year of operation in 1969, the
collection of the Regional Library has been strengthened
and the staff has increased both in number and in profes-
sional expertise. BIREME has performed 218,000 loan
services; prepared 5,255 special bibliographies; obtained
and donated 266,000 journal issues to other Latin
libraries and has provided specialized training to 263
Latin health science librarians.
As a result of the meeting of the Latin American
Ministers in 1972, PAHO and BIREME have entered into
agreements with Argentina, Peru, Chile, Colombia, Uruguay
and Venezuela. Each of these countries is in the process
of establishing a national center so that the transmittal
of services can be channeled between BIREME and that focus.
However, considerable effort is still needed to strengthen
these national entities and crystallize their relationships
into effective service linkages.
The success of this PAHO undertaking has demonstrated
that, even with political constraints and economic
considerations, it is possible to cross boundaries with
a regional/international effort devoted to the substance
of biomedicine and the provision of information services.
It is a recognition that improved biomedical communications
will assist in the advancement of medical research, edu-
cation and ultimately health care.
The World Health Organization has been interested in
developing such regional approaches in other areas of
the world. To date, no formal step has yet been taken.
International Organizations
The National Library of Medicine has continued its
membership in the International Council of Scientific
Unions Abstracting Board (ICSU AB) and participates in
128
the deliberations of this organization. The organization
is a meeting ground for information and abstracting organi-
zations, private and governmental, from a number of coun-
tries throughout the world, including the United Kingdom,
France, Germany, Poland, Japan, South Africa, Canada,
Belgium, The Netherlands and USSR. Important topics
under consideration by ICSU AB are standardization, the
economics of primary and secondary publications, the
relationships between primary and secondary services and
the information needs of developing countries. The 1976
meeting of ICSU AB will, be hosted by the National
Library of Medicine in Bethesda.
NIH ASSISTANCE TO WHO AND PAHO
During FY 1975 NIH continued to participate in acti-
vities of the international organizations, particularly
the World Health Organization (WHO) and the Pan American
Health Organization (PAHO) .
At the request of the Office of International
Health (OIH) , NIH program areas assisted in the review
of technical documents, working papers, and other program
materials, and participated in the formulation of U.S.
positions, many in connection with meetings of the
governing bodies of the World Health Organization (World
Health Assembly) , the Pan American Health Organization
(Pan American Sanitary Conference) , and the International
Agency for Research on Cancer (Governing Council) .
NCI and FIC continued to participate with the OIH
and the Department of State in defining the roles of
international cancer agencies, including WHO, IARC, and
the International Union against Cancer, and in defining
WHO's role in the development and coordination of
biomedical research. The NIH Director continued as a
member of the PAHO Advisory Committee on Medical Research.
NIH officials participated in formal meetings of
international organizations, including service on U.S.
delegations to meetings of their governing bodies. The
Deputy Director, NCI, served as the U.S. representative
to the 2-day annual meeting of the Governing Council of
the International Agency for Research on Cancer (14th
session, May 1975) and represented the United States at
the WHO meeting of heads . of medical research councils
(December 1974) .
The National Library of Medicine continued to col-
laborate with activities of the PAHO Regional Library of
Medicine, established at the Federal University of Sao
Paulo, Brazil, which provides services in the health
sciences to all of South America. The NLM Director
participated in the Seventh Meeting of the Scientific
Advisory Committee.
The Director, Center for Population Research, NICHD,
continued to serve on the Advisory Group to the WHO
Expanded Program of Research, Development, and Research
Training in Human Reproduction. This WHO program focuses
on the urgent need to develop a variety of safe, effective
and acceptable methods for the regulation of human fertility,
During FY 197 5, six NIH laboratories continued to
serve as Regional or International Collaborating Centers
129
130
for the World Health Organization; Collaborating Center
for Immunology, NCI; Collaborating Center for Malaria,
NIAID; Collaborating Center for Respiratory Viruses Other
Than Influenza, NIAID; Collaborating Center for Human
Rickettsioses, NIAID; Collaborating Center for Comparative
Medicine, NCI; and Collaborating Center for Mycoplasmas,
NIAID. In May 1974 the Division of Research Services,
NIH, was designated as the WHO Collaborating Center for
Defined Laboratory Animals.
Several NIH programs contracted to support specific
activities of PAHO, WHO, and IARC. NIAID, for example,
supported the First Inter-American Conference on Conserva-
tion and Utilization of American Nonhuman Primates in
Biomedical Research, held in Lima, Peru, June 2-4, 1975.
Some 50 NIH scientists served as advisors or consult-
ants to WHO/PAHO. Two NIH employees were on long-term
detail to WHO and one each to PAHO and IARC. An NLM
official, transferred to WHO, continued to serve as chief
of WHO's Library services. During the fiscal year many
NIH staff members continued to serve as members of a
variety of WHO expert advisory panels and participated
in their committee meetings.
Two programs (NIEHS and NIAID) were provided consult-
ant services by WHO. (This WHO activity provides "techni-
cal assistance" to U.S. domestic programs.)
131
UNITED STATES FELLOWS AND TRAINEES
ABROAD
The sponsoring of U.S. Fellows and Trainees for Re-
search and Training Abroad began with the establishment
of the several insitutes at NIH. The criteria originally
developed to select training locations for fellows and
trainees provided that they might attend any qualified
institution in the United States; study abroad was
authorized only when satisfactory evidence was provided
that the type or quality of training abroad was parti-
cularly suited for their purpose and could best be
obtained there. This program, which is administered
by the individual institutes, began with one fellowship
award made in 1947. The peak year for U.S. fellows and
trainees abroad was FY 1966 with 397 awards. Since FY
1966 foreign training has been reduced due to budgetary
controls.
GUEST WORKERS
Under the Guest Worker Program, the NIH may invite
individuals, other than employees or fellows of the NIH,
who are sponsored by qualified organizations to utilize
the research facilities of the NIH for the purpose of
carrying on a research project or participating in a
research program. The basis for acceptance of a guest
worker rests on complementary professional interest,
appropriate facilities, and the prospect of mutual
benefit to the host bureau, institute or division and
the guest worker. During FY 1975, 184 scientists from
42 countries worked at the NIH under this program.
*U.S. GOVERNMENT PRINTING OFFICE: 1976 621-710/2792 1-3
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